Atlas Journal

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 8, Number 3, Jul-Sep 2004 Previous Issue / Next Issue Genes BCAS3 (breast carcinoma amplified sequence 3)(17q23). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 367-369. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/BCAS3ID766.html BCAS4 (breast carcinoma amplified sequence 4) (20q13). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 370-372. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/BCAS4ID767.html C11ORF30 (chromosome 11 open reading frame 30) (11q13.4). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 373-375. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/C11ORF30ID173.html CHEK2 (CHK2 checkpoint homolog (S. pombe)) (22q12.1). Nancy Uhrhammer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 376-381. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CHEK2ID312.html LPP (lipoma preferred partner) (3q27-q28). Marleen M Petit. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 382-389. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/LPPID72.html MRE11A (11q21). Nancy Uhrhammer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 390-395. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 I URL : http://AtlasGeneticsOncology.org/Genes/MRE11ID247.html OLIG2 (21q22.11). David Rowitch. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 396-399. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/OLIG2ID236.html STAT3 (Signal Transducer and Activator of Transcription 3) (17q21.2). Brent H Cochran. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 400-406. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/STAT3ID444.html TFE3 (transcription factor E3) (Xp11.2) - updated. Roland P Kuiper. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 407-413. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TFE3ID86.html TFEB (transcription factor EB) (6p21). Roland P Kuiper. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 414-418. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TFEBID531.html CHFR (Checkpoint with fork-head associated and ring finger) (12q24.33). Ayse E Erson, Elizabeth M Petty. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 419-426. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CHFRID526.html DIRC1 (2q33). Anita Bonné, Eric Schoenmakers, Ad Geurts van Kessel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 427-429. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/DIRC1ID499.html FGA7 (Fused Gene 7 to AML1)(4q28). Fady M Mikhail, Giuseppina Nucifora. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 430-433. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/FGA7ID525.html HSPBAP1 (HSPB (heat shock 27kDa) associated protein 1) (3q21.1). Anita Bonné, Eric Schoenmakers, Ad Geurts van Kessel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 434-437. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/HSPBAP1ID513.html NQO1 (16q22.1) - updated. David Ross. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 438-448. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 II SERPINB5 (18q21.33). Jim Heighway, Shirley Smith, Naomi Bowers, Daniel Betticher. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 449-459. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SerpinB5ID42267.html TNF (tumor necrosis factor (TNF superfamily, member 2)) (6p21.3). Fei Chen. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 460-467. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TNFaID319.html TRC8 (translocation in renal carcinoma, chromosome 8 gene) (8q24.31). Anita Bonné, Eric Schoenmakers, Ad Geurts van Kessel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 468-471. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TRC8ID500.html BCL11B (B-cell lymphoma/leukaemia 11B) (14q32.2). Roderick A F MacLeod, Stefan Nagel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 472-479. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/BCL11BID392.html DDIT3 (DNA damage inducible transcript 3) (12q13.1-q13.2). Pedro A Pérez-Mancera, Isidro Sánchez-Garc&iicute;a. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 480-488. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/DDIT3ID80.html FUS (fusion involved in t(12;16) in malignant liposarcoma) (16p11.2). PA Pérez-Mancera, Isidro Sánchez-García. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 489-498. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/FUSID44.html Smad2, mothers against decapentaplegic homolog 2 (Drosophila) (18q21.1). Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 499-505. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SMAD2ID370.html Leukaemias t(2;3)(p15-23;q26-27). Marian Stevens-Kroef. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 506-508. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0203p15q26ID1091.html Multiple myeloma - updated. Franck Viguié. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 509-513. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/MMULID2038.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 III Polyclonal B Lymphocytosis with Binucleated Lymphocytes (PPBL). Xavier Troussard, Hossein Mossafa. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 514-517. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/PolyclonalLymphoID2040.html +6 or trisomy 6. Edmond SK Ma, Thomas SK Wan. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 518-522. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/tri6ID1013.html Solid Tumours Bone: Aneurysmal bone cysts - updated. Paola Dal Cin. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 523-527. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/AneurBoneCystID5133.html Lung: small cell cancer. Jim Heighway, Daniel C Betticher. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 528-533. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LungSmallCellID5142.html Kidney: Clear cell renal cell carcinoma. Eva van den Berg, Stephan Störkel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 534-540. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/ClearCellRenalCC5020.html Cancer Prone Diseases Deep Insights Deep insight into microarray technology. Claudia Schoch, Martin Dugas, Wolfgang Kern, Alexander Kohlmann, Susanne Schnittger, Torsten Haferlach. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (3): 541-563. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/MicroarraysID20045.html Case Reports Educational Items

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Atlas Genet Cytogenet Oncol Haematol 2004; 3 V Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCAS3 (breast carcinoma amplified sequence 3)

Identity Other MAAB names GAOB1 Hugo BCAS3 Location 17q23 DNA/RNA Description spans 715 kb; orientation direct strand; at least 77 exons Transcription alternate splicings: 3.9 kb, 3.3 kb, 2.3 kb, 1.5 kb, 1.3 kb. Protein

Expression ubiquitous Localisation nuclear (potential) Implicated in Entity BCAS3 is overexpressed in about 10% of breast cancers, and a hybrid gene BCAS4-BCAS3 was found in breat cancer cell line with a t(17;20)(q23;q13) Hybrid/Mutated 5' BCAS4 is fused to the 2 last exons (23 and 24) of BCAS3; Gene transcript includes exon 1 from BCAS4 and 21 bp from BCAS3 exon 23; it encodes a 66 aminoacids protein; no reciprocal transcript

External links Nomenclature Hugo BCAS3 GDB BCAS3 Entrez_Gene BCAS3 54828 breast carcinoma amplified sequence 3 Cards Atlas BCAS3ID766 GeneCards BCAS3 Ensembl BCAS3 CancerGene BCAS3 Genatlas BCAS3 GeneLynx BCAS3

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -367- eGenome BCAS3 euGene 54828 Genomic and cartography BCAS3 - 17q23 chr17:56110015-56824973 + 17q23.2 (hg17- GoldenPath May_2004) Ensembl BCAS3 - 17q23.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BCAS3 Gene and transcription

Genbank AF260268 [ SRS ] AF260268 [ ENTREZ ]

Genbank AF361219 [ SRS ] AF361219 [ ENTREZ ]

Genbank AJ511332 [ SRS ] AJ511332 [ ENTREZ ]

Genbank AJ518105 [ SRS ] AJ518105 [ ENTREZ ]

Genbank AJ518836 [ SRS ] AJ518836 [ ENTREZ ]

RefSeq NM_017679 [ SRS ] NM_017679 [ ENTREZ ]

RefSeq NT_086883 [ SRS ] NT_086883 [ ENTREZ ] AceView BCAS3 AceView - NCBI TRASER BCAS3 Traser - Stanford

Unigene Hs.463702 [ SRS ] Hs.463702 [ NCBI ] HS463702 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 607470 [ map ] GENECLINICS 607470

SNP BCAS3 [dbSNP-NCBI]

SNP NM_017679 [SNP-NCI]

SNP BCAS3 [GeneSNPs - Utah] BCAS3 [SNP - CSHL] BCAS3] [HGBASE - SRS] General knowledge Family BCAS3 [UCSC Family Browser] Browser SOURCE NM_017679 SMD Hs.463702 SAGE Hs.463702 Amigo component|nucleus PubGene BCAS3 Other databases Probes Probe BCAS3 Related clones (RZPD - Berlin)

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -368- PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Cloning of BCAS3 (17q23) and BCAS4 (20q13) genes that undergo amplification, overexpression, and fusion in breast cancer. Genes Chromosomes Cancer. 2002; 35: 311-317. Barlund M, Monni O, Weaver JD, Kauraniemi P, Sauter G, Heiskanen M, Kallioniemi OP, Kallioniemi A. Medline 12378525

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Jean-Loup Huret, Sylvie Senon 2004 Citation This paper should be referenced as such : Huret JL, Senon S . BCAS3 (breast carcinoma amplified sequence 3). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BCAS3ID766.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -369- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCAS4 (breast carcinoma amplified sequence 4)

Identity Other BHLHB4 names FLJ20495 Hugo BCAS4 Location 20q13 DNA/RNA Description spans 82 kb; orientation direct strand; 19 exons Transcription alternate splicings Protein

Expression ubiquitous Localisation cytoplasmic Implicated in Entity BCAS4 is overexpressed in 3.5% of breast cancers, and a hybrid gene BCAS4-BCAS3 was found in breat cancer cell line with a t(17;20)(q23;q13) Hybrid/Mutated 5' BCAS4 is fused to the 2 last exons (23 and 24) of BCAS3; Gene transcript includes exon 1 from BCAS4 and 21 bp from BCAS3 exon 23; it encodes a 66 aminoacids protein; no reciprocal transcript

External links Nomenclature Hugo BCAS4 GDB BCAS4 Entrez_Gene BCAS4 55653 breast carcinoma amplified sequence 4 Cards Atlas BCAS4ID767 GeneCards BCAS4 Ensembl BCAS4 CancerGene BCAS4 Genatlas BCAS4

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -370- GeneLynx BCAS4 eGenome BCAS4 euGene 55653 Genomic and cartography BCAS4 - 20q13 chr20:48844874-48927120 + 20q13.13 (hg17- GoldenPath May_2004) Ensembl BCAS4 - 20q13.13 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BCAS4 Gene and transcription

Genbank AL133228 [ SRS ] AL133228 [ ENTREZ ]

Genbank AF361220 [ SRS ] AF361220 [ ENTREZ ]

Genbank AJ511266 [ SRS ] AJ511266 [ ENTREZ ]

Genbank AK000502 [ SRS ] AK000502 [ ENTREZ ]

Genbank BC038381 [ SRS ] BC038381 [ ENTREZ ]

RefSeq NM_001010974 [ SRS ] NM_001010974 [ ENTREZ ]

RefSeq NM_017843 [ SRS ] NM_017843 [ ENTREZ ]

RefSeq NM_198799 [ SRS ] NM_198799 [ ENTREZ ]

RefSeq NT_086910 [ SRS ] NT_086910 [ ENTREZ ] AceView BCAS4 AceView - NCBI TRASER BCAS4 Traser - Stanford

Unigene Hs.381178 [ SRS ] Hs.381178 [ NCBI ] HS381178 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q8TDM0 [ SRS] Q8TDM0 [ EXPASY ] Q8TDM0 [ INTERPRO ] CluSTr Q8TDM0 Blocks Q8TDM0 Polymorphism : SNP, mutations, diseases OMIM 607471 [ map ] GENECLINICS 607471

SNP BCAS4 [dbSNP-NCBI]

SNP NM_001010974 [SNP-NCI]

SNP NM_017843 [SNP-NCI]

SNP NM_198799 [SNP-NCI]

SNP BCAS4 [GeneSNPs - Utah] BCAS4 [SNP - CSHL] BCAS4] [HGBASE - SRS] General knowledge Family BCAS4 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -371- SOURCE NM_001010974 SOURCE NM_017843 SOURCE NM_198799 SMD Hs.381178 SAGE Hs.381178 PubGene BCAS4 Other databases Probes Probe BCAS4 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Cloning of BCAS3 (17q23) and BCAS4 (20q13) genes that undergo amplification, overexpression, and fusion in breast cancer. Genes Chromosomes Cancer. 2002; 35: 311-317. Barlund M, Monni O, Weaver JD, Kauraniemi P, Sauter G, Heiskanen M, Kallioniemi OP, Kallioniemi A. Medline 12378525

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Jean-Loup Huret, Sylvie Senon 2004 Citation This paper should be referenced as such : Huret JL, Senon S . BCAS4 (breast carcinoma amplified sequence 4). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BCAS4ID767.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -372- Atlas of Genetics and Cytogenetics in Oncology and Haematology

C11ORF30 (chromosome 11 open reading frame 30)

Identity Other EMSY names GL002 ENT0 Hugo C11ORF30 Location 11q13.4 or .5 CCND1 is also at 11q13 DNA/RNA Description The gene spans 107 kb; on direct strand Transcription at least 11 transcripts; one transcript of 4kb and 21 exons encodes a protein of 1323 amino acids and 141 kDa. Protein

Localisation nucleus Function binds BRCA2 at its N-term transactivation domain; may repress the transcritional activity of BRCA2 Implicated in Entity C11ORF30/EMSY was found amplified in 7 and 17 % of cases respectively of sporadic breast cancers and high grade ovarian cancers, but very rarely in other cancers tested. Note 11q13 is frequently amplified in sporadic breast cancers; CCND1, in particular, is amplified in about 20% of cases. However, C11ORF30/EMSY was found amplified in cases with normal CCND1: they are independant factors. Prognosis C11ORF30/EMSY amplification is associated with a worse prognosis in node-negative breast cancers, and has no prgnosis implication in node- positive breast cancers.

External links Nomenclature Hugo C11ORF30 GDB C11orf30

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -373- Entrez_Gene C11orf30 56946 chromosome 11 open reading frame 30 Cards Atlas C11ORF30 GeneCards C11orf30 Ensembl C11orf30 CancerGene C11orf30 Genatlas C11orf30 GeneLynx C11orf30 eGenome C11orf30 euGene 56946 Genomic and cartography C11orf30 - 11q13.4 or .5 chr11:75833717-75940236 + 11q13.5 GoldenPath (hg17-May_2004) Ensembl C11orf30 - 11q13.5 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene C11orf30 Gene and transcription

Genbank AF226047 [ SRS ] AF226047 [ ENTREZ ]

Genbank AJ430203 [ SRS ] AJ430203 [ ENTREZ ]

Genbank AK023651 [ SRS ] AK023651 [ ENTREZ ]

Genbank AK125114 [ SRS ] AK125114 [ ENTREZ ]

Genbank AK126030 [ SRS ] AK126030 [ ENTREZ ]

RefSeq NM_020193 [ SRS ] NM_020193 [ ENTREZ ]

RefSeq NT_086784 [ SRS ] NT_086784 [ ENTREZ ] AceView C11orf30 AceView - NCBI TRASER C11orf30 Traser - Stanford

Unigene Hs.352588 [ SRS ] Hs.352588 [ NCBI ] HS352588 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 608573 [ map ] GENECLINICS 608573

SNP C11orf30 [dbSNP-NCBI]

SNP NM_020193 [SNP-NCI]

SNP C11orf30 [GeneSNPs - Utah] C11orf30 [SNP - CSHL] C11orf30] [HGBASE - SRS] General knowledge Family C11orf30 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -374- SOURCE NM_020193 SMD Hs.352588 SAGE Hs.352588 Amigo process|DNA repair Amigo process|chromatin modification Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent PubGene C11orf30 Other databases Probes Probe C11ORF30 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T. Cell. 2003; 115: 523-535. Medline 14651845

The hunt for BRCA2 interactors scores a big hit: EMSY as a prognostic tool for sporadic breast cancer. Slow E. Clin Genet. 2004; 65: 261-262. Medline 15025715 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Jean-Loup Huret, Sylvie Senon 2004 Citation This paper should be referenced as such : Huret JL, Senon S . C11ORF30 (chromosome 11 open reading frame 30). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/C11ORF30ID173.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -375- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CHEK2 (CHK2 checkpoint homolog (S. pombe))

Identity Other CHK2 names CDS1 Rad53 Hugo CHEK2 Location 22q12.1 DNA/RNA Description 17 exons spanning 57 kb Transcription Two isoforms are expressed, isoform a (2547nt) includes all 17 exons, while isoform b (2460 nt) does not include exon 12, deleting 87nt (29 codons) from the mRNA. The translation start site is in exon 4. Protein

Description 61 kDa. Isoform a: 543 amino acids; isoform b: 514 amino acids. Contains FHA and ser/thr kinase domains. Molecular studies of Chk2 typically do not distinguish between the different isoforms. Expression All tissues tested. Localisation nuclear Function Chk2 plays a role in the DNA damage signal cascade, especially in response to double-strand breaks. After detection of DNA damage, Chk2 is phosphorylated on Thr-68 by ATM and ATR. Thus activated, Chk2 targets p53 for phosphorylation on Ser20, releasing p53 from its inhibitor MDM2 and allowing transcriptional activation of genes responsible for cell cycle arrest, such as p21waf1/cip1, as well as initiation of apoptosis. In S phase, Chk2 phosphorylates Cdc25A on Ser123, targeting it for degradation and making it unavailable for the activation of cdk2, thus inhibiting the advance of S phase. In G2 phase, Chk2 phosphorylates Ser216 of Cdc25C, blocking entry into mitosis.

Chk2 is also involved in the regulation of BRCA1. Under normal conditions the two proteins are associated; after irradiation Chk2 phosphorylates Ser988 of BRCA1. This step is required for their dissociation, and the liberated BRCA1 participates directly in DNA repair and cell cycle arrest.

Finally, Chk2 can provoke apoptosis independently of p53, for example

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -376- via phosphorylation of PML. Homology 26 % identical to the Rad53 S. cereviscea homolog. The FHA and kinase domains are particularly conserved. Mutations Germinal The northern european founder mutation "1100delC" is the most common found in breast cancer families. Other small deletions, stops, and missense mutations in the FHA or kinase domains such as Arg145Trp and Ile157Thr are rare in cancer families but not found in controls. The 1100delC mutation appears to increase the penetrance of mutations in certain other breast cancer genes, notably BRCA2. It should be noted that the publications describing "1100delC" have used the A of the initiation codon as nucleotide 1. This mutation thus corresponds to position 1861 in the complete, isoform a mRNA. Somatic Missense mutations in the FHA and kinase domains as well as frameshifts and nonsense mutations have been found at low frequencies in osteosarcoma and more rarely in carcinomas of the ovary, lung, and vulva. Reduced or missing protein expression has been observed in some cases of non-Hodgkins lymphoma, although neither mutation nor silencing of the gene by methylation was detected. Implicated in Entity Li-Fraumeni, Li-Fraumeni-like syndrome, somatic osteosarcoma and familial aggregations of breast cancer and colon cancer. Note The importance of Chk2 mutations in hereditary cancer risk is controversial, as some studies have failed to show an excess of mutations in selected populations, such as male breast cancer and patients with multiple colorectal adenomas developing colon cancer. In addition, some studies of breast cancer families suggest that only the relatively frequent 1100delC mutation is significant. Prognosis No known association with the clinical parameters of solid tumors. There is a possible association with more agressive non-Hodgkins lymphomas.

External links Nomenclature Hugo CHEK2 GDB CHEK2 Entrez_Gene CHEK2 11200 CHK2 checkpoint homolog (S. pombe) Cards Atlas CHEK2ID312 GeneCards CHEK2 Ensembl CHEK2 CancerGene CHEK2

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -377- Genatlas CHEK2 GeneLynx CHEK2 eGenome CHEK2 euGene 11200 Genomic and cartography CHEK2 - 22q12.1 chr22:27408285-27462376 - 22q12.1 (hg17- GoldenPath May_2004) Ensembl CHEK2 - 22q12.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CHEK2 Gene and transcription

Genbank AL117330 [ SRS ] AL117330 [ ENTREZ ]

Genbank AL121825 [ SRS ] AL121825 [ ENTREZ ]

Genbank AB040105 [ SRS ] AB040105 [ ENTREZ ]

Genbank AF086904 [ SRS ] AF086904 [ ENTREZ ]

Genbank AF096279 [ SRS ] AF096279 [ ENTREZ ]

RefSeq NM_001005735 [ SRS ] NM_001005735 [ ENTREZ ]

RefSeq NM_007194 [ SRS ] NM_007194 [ ENTREZ ]

RefSeq NM_145862 [ SRS ] NM_145862 [ ENTREZ ]

RefSeq NT_086921 [ SRS ] NT_086921 [ ENTREZ ] AceView CHEK2 AceView - NCBI TRASER CHEK2 Traser - Stanford

Unigene Hs.291363 [ SRS ] Hs.291363 [ NCBI ] HS291363 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O96017 [ SRS] O96017 [ EXPASY ] O96017 [ INTERPRO ]

Prosite PS50006 FHA_DOMAIN [ SRS ] PS50006 FHA_DOMAIN [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Interpro IPR000253 FHA [ SRS ] IPR000253 FHA [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ]

Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -378- Interpro IPR008984 SMAD_FHA [ SRS ] IPR008984 SMAD_FHA [ EBI ] CluSTr O96017

Pfam PF00498 FHA [ SRS ] PF00498 FHA [ Sanger ] pfam00498 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00240 FHA [EMBL]

Smart SM00220 S_TKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom O96017 CHK2_HUMAN [ Domain structure ] O96017 CHK2_HUMAN [ sequences sharing at least 1 domain ] Blocks O96017

PDB 1GXC [ SRS ] 1GXC [ PdbSum ], 1GXC [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 604373 [ map ] GENECLINICS 604373

SNP CHEK2 [dbSNP-NCBI]

SNP NM_001005735 [SNP-NCI]

SNP NM_007194 [SNP-NCI]

SNP NM_145862 [SNP-NCI]

SNP CHEK2 [GeneSNPs - Utah] CHEK2 [SNP - CSHL] CHEK2] [HGBASE - SRS] General knowledge Family CHEK2 [UCSC Family Browser] Browser SOURCE NM_001005735 SOURCE NM_007194 SOURCE NM_145862 SMD Hs.291363 SAGE Hs.291363 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo process|DNA damage checkpoint Amigo process|cell cycle Amigo function|kinase activity Amigo component|nucleus Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo function|protein serine/threonine kinase activity Amigo function|protein-tyrosine kinase activity Amigo process|response to DNA damage stimulus

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -379- Amigo function|transferase activity BIOCARTA ATM Signaling Pathway BIOCARTA Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility BIOCARTA Cell Cycle: G2/M Checkpoint BIOCARTA Regulation of cell cycle progression by Plk3 PubGene CHEK2 Other databases Probes Probe CHEK2 Related clones (RZPD - Berlin) PubMed PubMed 58 Pubmed reference(s) in LocusLink Bibliography Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Matsuoka S, Huang M, Elledge SJ. Science 1998; 282: 1893-1897. Medline 9836640

DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Dasika GK, Lin SC, Zhao S, Sung P, Tomkinson A, Lee EY. Oncogene 1999; 18: 7883-7899. Review. Medline 10630641 p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomaki K, Nevanlinna H. Cancer Res 2001; 61: 5718-5722. Medline 11479205

Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Miller CW, Ikezoe T, Krug U, Hofmann WK, Tavor S, Vegesna V, Tsukasaki K, Takeuchi S, Koeffler HP. Genes Chromosomes Cancer 2002; 33(1): 17-21. Medline 11746983

Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Lipton L, Fleischmann C, Sieber OM, Thomas HJ, Hodgson SV, Tomlinson IP, Houlston RS. Cancer Lett 2003; 200(2): 149-152. Medline 14568168

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -380-

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, Evans DG, Eccles D, Meijers C, Lohman F, Klijn J, van den Ouweland A, Futreal PA, Nathanson KL, Weber BL, Easton DF, Stratton MR, Rahman N; Breast Cancer Linkage Consortium. Am J Hum Genet 2003; 72: 1023-1028. Medline 12610780

CHEK2 1100delC is not a risk factor for male breast cancer population. Syrjakoski K, Kuukasjarvi T, Auvinen A, Kallioniemi OP. Int J Cancer 2004; 108(3): 475-476. Medline 14648717

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Nancy Uhrhammer 2004 Citation This paper should be referenced as such : Uhrhammer N . CHEK2 (CHK2 checkpoint homolog (S. pombe)). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CHEK2ID312.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -381- Atlas of Genetics and Cytogenetics in Oncology and Haematology

LPP (lipoma preferred partner)

Identity Hugo LPP Location 3q27-q28 DNA/RNA

Description At least 11 exons; predicted start codon in exon 3, stop codon in exon 11; the protein coding region is covered by the overlapping "CEPH Mark 1" YAC clones 135H6 and 192B10 (start codon in 135H6, stop codon in 192B10) and is dispersed over at least 400 kb genomic DNA; the LIM domains are encoded by separate exons: LIM 1 is encoded by exon 8, LIM 2 by exon 9, and LIM 3 by exon 10 and part of exon 11. Transcription mRNA: ubiquitously: > 10 kb; testis: additional transcripts of 1.8 kb and 1.25 kb Pseudogene no pseudogenes Protein

Description 612 amino acids; proline-rich region (amino-terminal 2/3 of the protein) followed by three LIM domains (carboxy-terminal 1/3 of the protein).

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -382- Proline-rich region contains an alfa-actinin binding site, two VASP- binding motifs, and a nuclear export signal. Expression Smooth muscle marker; readily detected on Western blot with an LPP- antibody in all fibroblastic and epithelial cell lines tested to date. Localisation LPP is present in the cytoplasm of cells as well as at sites of cell adhesion such as focal adhesions (attachments sites to the extracellular matrix) and cell-cell contacts; LPP also shuttles to the nucleus and its nuclear-cytoplasmic localisation is regulated in part by a nuclear export signal (NES) which is sensitive to the drug leptomycin B. Function Because of their structural features (many protein-protein interaction domains) and their characteristic to shuttle between the nucleus and the cytoplasm, LPP and its family members (see below) have been proposed to be scaffolding proteins involved in signal transduction from sites of cell adhesion to the nucleus; LPP has been shown to harbour transcriptional activation capacity in luciferase reporter assays, suggesting that LPP may be directly involved in the regulation of gene expression; LPP was found to be highly expressed in smooth muscle, and a role for LPP in regulating cell motility was proposed; the precise function of LPP remains to be elucidated. Homology LPP is a member of the zyxin family of proteins, which contains five members: ajuba, LIMD1, LPP, TRIP6 and zyxin. The family hallmark of these proteins are three clustered LIM domains at the carboxy-terminus, which are protein interaction domains. All family members are present at sites of cell adhesion and have the ability to shuttle to the nucleus, and all family members have one or more nuclear export signals. Mutations Somatic HMGA2/LPP fusion proteins and MLL/LPP fusion proteins (Fig2). Implicated in Entity solitary lipomas Disease Benign tumors of adipose tissue. Prognosis Can be surgically removed with no recurrence in most cases. Cytogenetics More than 60% of solitary lipomas have an aberrant karyotype; 2/3 of these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene; 1/4 of the latter have chromosomal region 3q27-q28 (containing LPP) as 12q15 translocation partner as such creating an HMGA2/LPP fusion gene. Hybrid/Mutated HMGA2/LPP hybrid gene containing the first three exons of HMGA2 Gene and exons 8-11 or 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal HMGA2/LPP fusion transcripts encode the three DNA-binding Protein domains of HMGA2 followed by two LIM domains (LIM 2 and LIM 3) or a portion of the proline-rich region and all three LIM domains of LPP.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -383-

Entity Pulmonary chondroid hamartomas Disease Benign mesenchymal tumors of the lung. Prognosis good Cytogenetics More than 70% of pulmonary chondroid hamartomas have an aberrant karyotype; 70% of these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene; 1/8 of the latter have chromosomal region 3q27-q28 (containing LPP) as 12q15 translocation partner as such creating an HMGA2/LPP fusion gene. Hybrid/Mutated HMGA2/LPP hybrid gene containing the first three exons of HMGA2 Gene and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal HMGA2/LPP fusion transcripts encode the three DNA-binding Protein domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -384- Entity Parosteal lipoma Disease Rare deep-seated benign tumor of adipose tissue comprising less than 0.5% of all lipomas; parosteal lipomas exhibit a contiguous relationship with the periostium; because of their intimate relationship to the bone, they are considered as lipomas of bone. Prognosis Most often asymptomatic; in some cases: loss of motor and/or sensory function as a result of the compression or stretching of a nerve. Cytogenetics One case reported with rearrangement of LPP t(3;12)(q28;q14). Hybrid/Mutated HMGA2/LPP hybrid gene containing the first three exons of HMGA2 Gene and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal HMGA2/LPP fusion transcripts encode the three DNA-binding Protein domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP.

Entity Soft tissue chondroma Disease Benign tumor of cartilage; rare entity. Cytogenetics Only 31 cases with abnormal karyotypes have been reported (11- 2003); 12q15 nonrandomly involved; one case reported with rearrangement of LPP t(3;12)(q27;q15). Hybrid/Mutated HMGA2/LPP hybrid gene containing the first three exons of HMGA2 Gene and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal HMGA2/LPP fusion transcripts encode the three DNA-binding Protein domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP.

Entity AML-M5 Disease Secondary leukemia following treatment with DNA topoisomerase II inhibitors. Cytogenetics MLL gene on 11q23 frequently involved; one case reported with rearrangement of LPP t(3;11)(q28;q23). Hybrid/Mutated MLL/LPP hybrid gene containing the first 8 exons of MLL and exons Gene 9-11 of LPP; under the regulation of the MLL promoter. Abnormal MLL/LPP fusion transcripts encode the three DNA-binding domains Protein and the methyltransferase-like domain of MLL followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP.

External links Nomenclature Hugo LPP

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -385- GDB LPP LPP 4026 LIM domain containing preferred translocation partner in Entrez_Gene lipoma Cards Atlas LPPID72 GeneCards LPP Ensembl LPP CancerGene LPP Genatlas LPP GeneLynx LPP eGenome LPP euGene 4026 Genomic and cartography GoldenPath LPP - chr3:189413423-190078534 + 3q27.3 (hg17-May_2004) Ensembl LPP - 3q27.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene LPP Gene and transcription

Genbank A52566 [ SRS ] A52566 [ ENTREZ ]

Genbank A79998 [ SRS ] A79998 [ ENTREZ ]

Genbank U49968 [ SRS ] U49968 [ ENTREZ ]

Genbank AL833171 [ SRS ] AL833171 [ ENTREZ ]

Genbank CR457074 [ SRS ] CR457074 [ ENTREZ ]

RefSeq NM_005578 [ SRS ] NM_005578 [ ENTREZ ]

RefSeq NT_086644 [ SRS ] NT_086644 [ ENTREZ ] AceView LPP AceView - NCBI TRASER LPP Traser - Stanford

Unigene Hs.444362 [ SRS ] Hs.444362 [ NCBI ] HS444362 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q93052 [ SRS] Q93052 [ EXPASY ] Q93052 [ INTERPRO ]

Prosite PS00478 LIM_DOMAIN_1 [ SRS ] PS00478 LIM_DOMAIN_1 [ Expasy ]

Prosite PS50023 LIM_DOMAIN_2 [ SRS ] PS50023 LIM_DOMAIN_2 [ Expasy ]

Interpro IPR001781 LIM [ SRS ] IPR001781 LIM [ EBI ] CluSTr Q93052

Pfam PF00412 LIM [ SRS ] PF00412 LIM [ Sanger ] pfam00412 [ NCBI-CDD ]

Smart SM00132 LIM [EMBL]

Prodom PD000094 LIM[INRA-Toulouse]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -386- Prodom Q93052 Q93052 [ Domain structure ] Q93052 Q93052 [ sequences sharing at least 1 domain ] Blocks Q93052 Polymorphism : SNP, mutations, diseases OMIM 600700 [ map ] GENECLINICS 600700

SNP LPP [dbSNP-NCBI]

SNP NM_005578 [SNP-NCI]

SNP LPP [GeneSNPs - Utah] LPP [SNP - CSHL] LPP] [HGBASE - SRS] General knowledge Family LPP [UCSC Family Browser] Browser SOURCE NM_005578 SMD Hs.444362 SAGE Hs.444362 Amigo process|biological_process unknown Amigo component|cellular_component unknown Amigo function|zinc ion binding PubGene LPP Other databases Probes Probe LPP Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Petit MMR, Mols R, Schoenmakers EF, Mandahl N, Van de Ven WJM. Genomics 1996; 36: 118-129. Medline 8812423

Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma. Petit MMR, Swarts S, Bridge JA, Van de Ven WJM. Cancer Genet Cytogenet 1998; 106: 18-23. Medline 9772904

The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Rogalla P, Kazmierczak B, Meyer-Bolte K, Tran KH, Bullerdiek J. Genes Chromosomes Cancer 1998; 22: 100-104.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -387- Medline 9598796

LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity. Petit MMR, Fradelizi J, Golsteyn RM, Ayoubi TAY, Menichi B, Louvard D, Van de Ven WJM, Friederich E. Mol Biol Cell 2000; 11: 117-129. Medline 10637295

Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). Daheron L, Veinstein A, Brizard F, Drabkin H, Lacotte L, Guilhot F, Larsen CJ, Brizard A, Roche J. Genes Chromosomes Cancer 2001; 31: 382-389. Medline 11433529

A novel LPP fusion gene indicates the crucial role of truncated LPP proteins in lipomas and pulmonary chondroid hamartomas. Lemke I, Rogalla P, Bullerdiek J. Cytogenet Cell Genet 2001; 95: 153-156. Medline 12063392

Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Dahlen A, Mertens F, Rydholm A, Brosjo O, Wejde J, Mandahl N, Panagopoulos I. Mod Pathol 2003; 16: 1132-1140. Medline 14614053

LPP, a LIM protein highly expressed in smooth muscle. Gorenne I, Nakamoto RK, Phelps CP, Beckerle MC, Somlyo AV, Somlyo AP. Am J Physiol Cell Physiol 2003; 285: C674-685. Medline 12760907

The lipoma preferred partner LPP interacts with alpha-actinin. Li B, Zhuang L, Reinhard M, Trueb B. J Cell Sci 2003; 116: 1359-1366. Medline 12615977

Prediction of cell type-specific gene modules: identification and initial characterization of a core set of smooth muscle-specific genes. Nelander S, Mostad P, Lindahl P. Genome Res 2003; 13: 1838-1854 Medline 12869577

The focal adhesion and nuclear targeting capacity of the LIM-containing lipoma-preferred partner (LPP) protein.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -388- Petit MMR, Meulemans SMP, Van de Ven WJM. J Biol Chem 2003; 278: 2157-2168. Medline 12441356

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Marleen M Petit 2004 Citation This paper should be referenced as such : Petit MM . LPP (lipoma preferred partner). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/LPPID72.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -389- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MRE11A

Identity Note Pseudogenes have been localized to chromosomes 3q25 and 7q11.2- q11.3. Other MRE11 names ATLD HNGS1 Hugo MRE11A Location 11q21 DNA/RNA Description 22 exons spanning 76 kb Transcription Two isoforms are expressed, isoform 1 at 4772nt; isoform 2, 4688 nt, transcribed from an alternative first (noncoding) exon and lacking exon 5. Protein

Description Both isoforms are approximately 80 kDa. Isoform 1 includes 708 amino acids; isoform 2 includes 680. Molecular studies of Mre11 typically do not distinguish between the different isoforms. Mre11 is a subunit of the Rad50/Mre11/NBS1 (R/M/N) complex and serves as a single-strand DNA endonuclease, a 3' to 5' DNA exonuclease, and to open hairpin DNA structures. Expression All tissues examined, with higher levels in proliferating tissues. Localisation Nuclear. Function Mre11 participates in the repair of DNA double-strand breaks and replication errors as well as in meiotic homologous recombination. The R/M/N complex is part of the BRCA1-associated genome surveillance complex (BASC). The phosphorylation of Mre11 and NBS1 by another member of this super-complex, ATM, is essential for an early step in the response to DNA double-strand breaks (DSBs) and for their repair by either non-homologous end joining (NHEJ) or homologous recombination (HR). The interaction of DNA end-bound Mre11 with Ku70 may direct the break to rejoining by NHEJ, while the absense of Ku70 favors repair by HR. Current models propose DSB detection by R/M/N is required for the activation of ATM, which in turn phosphorylates Mre11 and NBS1, thus placing Mre11 both upstream

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -390- and downstream of ATM in the DNA damage response signal transduction cascade.

A mechanism has been proposed in which each end of a DNA DSB is bound by an R/M/N dimer, the two dimers being held to each other via the Zinc-hook domain of each Rad50 unit. As the Zinc-hook of Rad50 is located at the end of a long coiled-coil domain, this provides a flexible structure in which each DNA end is accessible to additional repair enzymes while being held in close proximity to each other in preparation for re-ligation.

Cells lacking Mre11 are deficient in DSB repair, and exhibit hypersensitivity to DNA damaging agents such as ionizing radiation and radiomimetic drugs. Such cells also have abnormal DNA replication and high levels of chromosomal instability. Homology The gene is conserved throughout eukaryotes, with 70% nucleic acid homology to S. cerevisiea Mre11. Mutations Germinal The hypomorphic arg633ter, asn117ser and arg571ter alleles have been described in ATLD patients. Homozygosity for null alleles is thought to be lethal in embryogenesis, as is the case in Mre11 knockout mice. Germline mutations have also been found in sporadic hematopoetic malignancies, with loss of the wild-type allele in the malignant cells. Somatic Rare mutations have been found in breast cancer and lymphoma. In colon cancers not expressing Mre11, the mutation of a poly-T tract in intron 4 has been shown to induce a splicing error that truncates the protein. Seven of 20 gastric tumors failed to express Mre11, although the cause of this was not demonstrated. Implicated in Entity Ataxia telangiectasia - like disorder (ATLD) Disease Ataxia telangiectasia-like disorder is a progressive cerebellar degenerative disease with telangiectasia, immunodeficiency, cancer risk, radiosensitivity, and chromosomal instability. Only a very few ATLD patients are known, in spite of the suggestion that as many as 6% of "A-T" patients may in fact have mutations in Mre11 (this figure is calculated be comparing the size (and thus the opportunity for mutation) of the two genes, as well as the observation that a small minority of A-T patients express apparently normal ATM and for whom no ATM mutation has been detected). The two disorders cannot be distinguished by their phenotypes, though there is some indication that ATLD may have a milder course. The severity of the disease may be dependent on the residual activity of the mutated Mre11 alleles. Prognosis Poor, though the course of the disease may be milder than found in classic A-T. Cytogenetics Spontaneous chromatid/chromosome breaks; non clonal stable

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -391- chromosome rearrangements involving immunoglobulin superfamily genes e.g. inv(7)(p14q35); clonal rearrangements.

External links Nomenclature Hugo MRE11A GDB MRE11A MRE11A 4361 MRE11 meiotic recombination 11 homolog A (S. Entrez_Gene cerevisiae) Cards Atlas MRE11ID247 GeneCards MRE11A Ensembl MRE11A CancerGene MRE11A Genatlas MRE11A GeneLynx MRE11A eGenome MRE11A euGene 4361 Genomic and cartography MRE11A - 11q21 chr11:93790121-93866688 - 11q21 (hg17- GoldenPath May_2004) Ensembl MRE11A - 11q21 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MRE11A Gene and transcription

Genbank AF303395 [ SRS ] AF303395 [ ENTREZ ]

Genbank AY584241 [ SRS ] AY584241 [ ENTREZ ]

Genbank AF022778 [ SRS ] AF022778 [ ENTREZ ]

Genbank AF073362 [ SRS ] AF073362 [ ENTREZ ]

Genbank AK095388 [ SRS ] AK095388 [ ENTREZ ]

RefSeq NM_005590 [ SRS ] NM_005590 [ ENTREZ ]

RefSeq NM_005591 [ SRS ] NM_005591 [ ENTREZ ]

RefSeq NT_086787 [ SRS ] NT_086787 [ ENTREZ ] AceView MRE11A AceView - NCBI TRASER MRE11A Traser - Stanford

Unigene Hs.192649 [ SRS ] Hs.192649 [ NCBI ] HS192649 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -392- SwissProt P49959 [ SRS] P49959 [ EXPASY ] P49959 [ INTERPRO ]

Interpro IPR003701 DNA_repair [ SRS ] IPR003701 DNA_repair [ EBI ]

Interpro IPR004843 M-pesterase [ SRS ] IPR004843 M-pesterase [ EBI ] Interpro IPR007281 Mre11_DNA_bind [ SRS ] IPR007281 Mre11_DNA_bind [ EBI ] CluSTr P49959

PF00149 Metallophos [ SRS ] PF00149 Metallophos [ Sanger Pfam ] pfam00149 [ NCBI-CDD ]

PF04152 Mre11_DNA_bind [ SRS ] PF04152 Mre11_DNA_bind [ Sanger Pfam ] pfam04152 [ NCBI-CDD ] Blocks P49959 Polymorphism : SNP, mutations, diseases OMIM 600814 [ map ] GENECLINICS 600814

SNP MRE11A [dbSNP-NCBI]

SNP NM_005590 [SNP-NCI]

SNP NM_005591 [SNP-NCI]

SNP MRE11A [GeneSNPs - Utah] MRE11A [SNP - CSHL] MRE11A] [HGBASE - SRS] General knowledge Family MRE11A [UCSC Family Browser] Browser SOURCE NM_005590 SOURCE NM_005591 SMD Hs.192649 SAGE Hs.192649 Amigo function|3'-5' exonuclease activity Amigo process|double-strand break repair via nonhomologous end-joining Amigo function|double-stranded DNA binding Amigo function|hydrolase activity Amigo function|manganese ion binding Amigo process|meiosis Amigo process|meiotic recombination Amigo component|nucleoplasm Amigo process|regulation of mitotic recombination function|single-stranded DNA specific endodeoxyribonuclease Amigo activity Amigo process|telomerase-dependent telomere maintenance BIOCARTA ATM Signaling Pathway BIOCARTA Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -393- PubGene MRE11A Other databases Probes Probe MRE11A Related clones (RZPD - Berlin) PubMed PubMed 22 Pubmed reference(s) in LocusLink Bibliography Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M, Carroll D, Gautier J. Mol Cell 2001; 8(1): 137-147. Medline 11511367

The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Falck J, Petrini JH, Williams BR, Lukas J, Bartek J. Nat Genet 2002; 30(3): 290-294. Medline 11850621

Isolation and characterization of the human MRE11 homologue. Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR, Weaver DT. Genomics 1995; 29(1): 80-86. Medline 8530104

The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM. Cell 1999; 99(6): 577-587. Medline 10612394

BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. Genes Dev 2000; 14(8): 927-939. Medline 10783165

Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability. Giannini G, Rinaldi C, Ristori E, Ambrosini MI, Cerignoli F, Viel A, Bidoli E, Berni S, D'Amati G, Scambia G, Frati L, Screpanti I, Gulino A. Oncogene 2004; 23(15): 2640-2647. Medline 15048091

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -394-

Human MRE11 is inactivated in mismatch repair-deficient cancers. Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A, Ottini L, Crescenzi M, Martinotti S, Bignami M, Frati L, Screpanti I, Gulino A. EMBO Rep 2002; 3(3): 248-254. Medline 11850399

Alterations of the double-strand break repair gene MRE11 in cancer. Fukuda T, Sumiyoshi T, Takahashi M, Kataoka T, Asahara T, Inui H, Watatani M, Yasutomi M, Kamada N, Miyagawa K. Cancer Res 2001; 61(1): 23-26. Medline 11196167

The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA. Nature 2002; 418: 562-566. Medline 12152085

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Nancy Uhrhammer 2004 Citation This paper should be referenced as such : Uhrhammer N . MRE11A. Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MRE11ID247.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -395- Atlas of Genetics and Cytogenetics in Oncology and Haematology

OLIG2

Identity Other RK17 names Olg-2 Bhlhb1 RACK17 HGNC:13226 PRKCBP2 BHLHB1 Hugo OLIG2 Location 21q22.11 DNA/RNA Note OLIG2 is an essential transcriptional regulator in motoneuron and oligodendrocyte development. Protein

Description 329 amino acids; 32 kDa; contains 1 basic helix-loop-helix DNA-binding domain (bHLH). Expression Olig2 is expressed in the ventral thalamus of developing mice. Function Required for oligodendrocyte and motor neuron specification in the spinal cord. Implicated in Entity T-cell lymphoma Cytogenetics Translocation t(14;21)(q11.2;q22) Hybrid/Mutated T-cell receptor promoter translocated upstream of OLIG2. Gene Abnormal none Protein

Entity Brain cancer Disease Oligodendroglioma, astrocytoma, glioblastoma. Prognosis variable

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -396- Cytogenetics No known genetic abnormalities in OLIG2. Hybrid/Mutated n/a Gene Oncogenesis OLIG expression in brain cancer raises possibilities that it could regulate behavior of tumor cell populations but this has not been demonstrated.

External links Nomenclature Hugo OLIG2 GDB OLIG2 Entrez_Gene OLIG2 10215 oligodendrocyte lineage transcription factor 2 Cards Atlas OLIG2ID236 GeneCards OLIG2 Ensembl OLIG2 CancerGene PRKCBP2 Genatlas OLIG2 GeneLynx OLIG2 eGenome OLIG2 euGene 10215 Genomic and cartography OLIG2 - 21q22.11 chr21:33320163-33323371 + 21q22.11 GoldenPath (hg17-May_2004) Ensembl OLIG2 - 21q22.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene OLIG2 Gene and transcription

Genbank AF221520 [ SRS ] AF221520 [ ENTREZ ]

Genbank AK091462 [ SRS ] AK091462 [ ENTREZ ]

Genbank BC034681 [ SRS ] BC034681 [ ENTREZ ]

Genbank BC036245 [ SRS ] BC036245 [ ENTREZ ]

Genbank BC036275 [ SRS ] BC036275 [ ENTREZ ]

RefSeq NM_005806 [ SRS ] NM_005806 [ ENTREZ ]

RefSeq NT_086913 [ SRS ] NT_086913 [ ENTREZ ] AceView OLIG2 AceView - NCBI TRASER OLIG2 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -397- Unigene Hs.176977 [ SRS ] Hs.176977 [ NCBI ] HS176977 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q13516 [ SRS] Q13516 [ EXPASY ] Q13516 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ] CluSTr Q13516

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ] Blocks Q13516 Polymorphism : SNP, mutations, diseases OMIM 606386 [ map ] GENECLINICS 606386

SNP OLIG2 [dbSNP-NCBI]

SNP NM_005806 [SNP-NCI]

SNP OLIG2 [GeneSNPs - Utah] OLIG2 [SNP - CSHL] OLIG2] [HGBASE - SRS] General knowledge Family OLIG2 [UCSC Family Browser] Browser SOURCE NM_005806 SMD Hs.176977 SAGE Hs.176977 Amigo function|DNA binding Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent PubGene OLIG2 Other databases Probes Probe OLIG2 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene. Wang J, Jani-Sait SN, Escalon EA, Carroll AJ, de Jong PJ, Kirsch IR, Aplan PD. Proc Natl Acad Sci U S A 2000; 97(7): 3497-3502. Medline 10737801

Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -398- Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, Alzamora MG, Louis DN, Stiles CD, Rowitch DH, Black PM. Proc Natl Acad Sci U S A 2001; 98(19): 10851-10856. Medline 11526205

OLIG2 as a specific marker of oligodendroglial tumour cells. Marie Y, Sanson M, Mokhtari K, Leuraud P, Kujas M, Delattre JY, Poirier J, Zalc B, Hoang-Xuan K. Lancet 2001; 358: 298-300. Medline 11498220

OLIG-1 and 2 gene expression and oligodendroglial tumours. Hoang-Xuan K, Aguirre-Cruz L, Mokhtari K, Marie Y, Sanson M. Neuropathol Appl Neurobiol 2002; 28(2): 89-94. Medline 11972795

Immunolocalization of the oligodendrocyte transcription factor 1 (Olig1) in brain tumors. Azzarelli B, Miravalle L, Vidal R. J Neuropathol Exp Neurol 2004; 63(2): 170-179 Medline 14989603

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- David Rowitch 2004 Citation This paper should be referenced as such : Rowitch D . OLIG2. Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/OLIG2ID236.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -399- Atlas of Genetics and Cytogenetics in Oncology and Haematology

STAT3 (Signal Transducer and Activator of Transcription 3)

Identity Other Acute Phase Response Factor, APRF names Hugo STAT3 Location 17q21.2 STAT3 is flanked by STAT5a and PTRF DNA/RNA Note 24 exons spanning 74444 bp. Transcription There are two major transcripts, STAT3a and STAT3b. STAT3a mRNA is 4973 bp. The STAT3b arises due to an alternate splice acceptor site in exon 23 which gives rise to a protein that is essentially truncated after amino acid 715. Another variant differs by 1 amino acid. Protein

Description There are two major isoforms of STAT3. The long form is known as STAT3 (or STAT3a) and is a 770 amino acid protein (93 kDa on gels). Notable features are STAT family DNA binding domain, an SH2 domain, a major tyrosine phosphorylation site at Y705 and a major serine phosphorylation site at S727. Phosphorylation leads to dimerization of STAT3 via intermolecular pTyr-SH2 interactions. STAT3 can also heterodimerize with STAT1. (Recent data suggests that STAT3 can possibly form a dimmer without tyrosine phosphorylation and that phosphorylation leads to changes dimmer conformation). Tyrosine of the protein activates its high affinity DNA binding activity (TTCNNNGAA) and can stimulate nuclear translocation of the protein. Stimulation of STAT3 tyrosine phosphorylation occurs in response to a variety of cytokines and growth factors including LIF, OSM, IL-6, leptin, EGF, PDGF, and HGF. The C terminal domain is a transcriptional activation domain whose activity is enhanced by phosphorylation of serine 727.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -400- The STAT3 beta isoform (84 kDa) is missing this domain (1-715 + 7 unique amino acids resulting from frameshift) and is sometimes used as a dominant negative though there is also evidence that it regulates distinct genes as well. Expression near ubiquitous Localisation Cytoplasmic, but translocates to the nucleus upon tyrosine phosphorylation. Function Transcription regulation. Homology Shares homology with the other 6 mammalian STAT genes: STAT1, STAT2, STAT4, STAT5A, STAT5B, STAT6. Implicated in Disease Upregulated in many cancers including glioblastoma, head and neck cancer, prostate cancer, and breast cancer. A constitutively active form of STAT3 is oncogenic, though these mutations have not been identified in human cancer as yet. STAT 3 activation is associated with Crohn's disease, and other inflammatory diseases such as pulmonary fibrosis and acute lung injury. STAT3 is critical for leptin signaling and its mutation leads to obesity in mice.

External links Nomenclature Hugo STAT3 GDB STAT3 STAT3 6774 signal transducer and activator of transcription 3 Entrez_Gene (acute-phase response factor) Cards Atlas STAT3ID444 GeneCards STAT3 Ensembl STAT3 CancerGene STAT3 Genatlas STAT3 GeneLynx STAT3 eGenome STAT3 euGene 6774 Genomic and cartography STAT3 - 17q21.2 chr17:37718869-37794039 - 17q21.2 (hg17- GoldenPath May_2004) Ensembl STAT3 - 17q21.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -401- HomoloGene STAT3 Gene and transcription

Genbank AF332508 [ SRS ] AF332508 [ ENTREZ ]

Genbank AY572796 [ SRS ] AY572796 [ ENTREZ ]

Genbank AF029311 [ SRS ] AF029311 [ ENTREZ ]

Genbank AI631896 [ SRS ] AI631896 [ ENTREZ ]

Genbank AJ012463 [ SRS ] AJ012463 [ ENTREZ ]

RefSeq NM_003150 [ SRS ] NM_003150 [ ENTREZ ]

RefSeq NM_139276 [ SRS ] NM_139276 [ ENTREZ ]

RefSeq NM_213662 [ SRS ] NM_213662 [ ENTREZ ]

RefSeq NT_086877 [ SRS ] NT_086877 [ ENTREZ ] AceView STAT3 AceView - NCBI TRASER STAT3 Traser - Stanford

Unigene Hs.463059 [ SRS ] Hs.463059 [ NCBI ] HS463059 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P40763 [ SRS] P40763 [ EXPASY ] P40763 [ INTERPRO ]

Prosite PS50001 SH2 [ SRS ] PS50001 SH2 [ Expasy ]

IPR008967 P53_like_DNA_bnd [ SRS ] IPR008967 Interpro P53_like_DNA_bnd [ EBI ]

Interpro IPR000980 SH2 [ SRS ] IPR000980 SH2 [ EBI ]

Interpro IPR001217 STAT [ SRS ] IPR001217 STAT [ EBI ] CluSTr P40763

Pfam PF00017 SH2 [ SRS ] PF00017 SH2 [ Sanger ] pfam00017 [ NCBI-CDD ]

PF01017 STAT_alpha [ SRS ] PF01017 STAT_alpha [ Sanger Pfam ] pfam01017 [ NCBI-CDD ]

PF02864 STAT_bind [ SRS ] PF02864 STAT_bind [ Sanger Pfam ] pfam02864 [ NCBI-CDD ] Pfam PF02865 STAT_int [ SRS ] PF02865 STAT_int [ Sanger ] pfam02865 [ NCBI-CDD ] Blocks P40763 Polymorphism : SNP, mutations, diseases OMIM 102582 [ map ] GENECLINICS 102582

SNP STAT3 [dbSNP-NCBI]

SNP NM_003150 [SNP-NCI]

SNP NM_139276 [SNP-NCI]

SNP NM_213662 [SNP-NCI]

SNP STAT3 [GeneSNPs - Utah] STAT3 [SNP - CSHL] STAT3] [HGBASE - SRS] General knowledge

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -402- Family STAT3 [UCSC Family Browser] Browser SOURCE NM_003150 SOURCE NM_139276 SOURCE NM_213662 SMD Hs.463059 SAGE Hs.463059 Amigo process|JAK-STAT cascade Amigo process|acute-phase response Amigo function|calcium ion binding Amigo process|cell motility Amigo component|cytoplasm function|hematopoietin/interferon-class (D200-domain) cytokine Amigo receptor signal transducer activity Amigo process|intracellular signaling cascade Amigo process|negative regulation of transcription from Pol II promoter Amigo process|neurogenesis Amigo component|nucleus Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|signal transducer activity Amigo function|transcription factor activity Amigo function|transcription factor activity BIOCARTA TPO Signaling Pathway BIOCARTA EGF Signaling Pathway BIOCARTA Erk1/Erk2 Mapk Signaling pathway BIOCARTA Role of ERBB2 in Signal Transduction and Oncology BIOCARTA IL22 Soluble Receptor Signaling BIOCARTA IL 6 signaling pathway BIOCARTA Signaling of Hepatocyte Growth Factor Receptor BIOCARTA PDGF Signaling Pathway BIOCARTA Stat3 Signaling Pathway PubGene STAT3 Other databases Probes Probe STAT3 Related clones (RZPD - Berlin) PubMed PubMed 127 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -403- Bibliography Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91- related transcription factor involved in the gp130-mediated signaling pathway. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. Cell 1994; 77: 63-71. Medline 7512451

Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Zhong Z, Wen Z,Darnell JJ. Proc Natl Acad Sci U.S.A. 1994; 91: 4806-4810. Medline 7545930

Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Zhong Z, Wen Z,Darnell JJ. Science 1994; 264: 95-98. Medline 8140422

A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Horvath C, Wen Z,Darnell JJ. Genes & Development 1995; 9: 984-994. Medline 7774815

Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Wen Z, Zhong Z, Darnell JE, Jr. Cell 1995; 82: 241-250. Medline 7543024

STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JAM, Lammers JWJ, Koenderman L,de Groot RP. J Biol Chem 1996; 271: 13221-13227. Medline 8675499

Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP,Jove R. Cell Growth Differ 1997; 8: 1267-1276. Medline 9419415

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -404- Three-dimensional structure of the Stat3beta homodimer bound to DNA. Becker S, Groner B, Muller CW Nature 1998; 394: 145-151. Medline 9671298

Stat3 activation is required for cellular transformation by v-src. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE, Jr. Mol Cell Biol 1998; 18: 2553-2558. Medline 9566875

Stat3 as an oncogene. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE, Jr. Cell 1999; 98: 295-303. Medline 10458605

Roles of STAT3 defined by tissue-specific gene targeting. Akira S Oncogene 2000; 19: 2607-2611. Medline 10851059

Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Yoo JY, Huso DL, Nathans D,Desiderio S. Cell 2002; 108: 331-344. Medline 11853668

STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW,Myers MG, Jr. Nature 2003; 421: 856-859. Medline 12594516

STATs dimerize in the absence of phosphorylation. Braunstein J, Brutsaert S, Olson R,Schindler C J Biol Chem 2003; 278: 34133-34140. Medline 12832402

Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. Konnikova L, Kruger MM, Kotecki M, Cochran BH. BMC Cancer 2003; 3: 23. Medline 13678425

Constitutive STAT3 activation in intestinal T cells from patients with Crohn's

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -405- disease. Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, Eriksen KW, Woetmann A, Odum N. J Biol Chem 2003; 278: 16777-16781. Medline 12615922

A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation. Ma J, Zhang T, Novotny-Diermayr V, Tan AL, Cao X J Biol Chem 2003; 278: 29252-29260. Medline 12746441

The STAT3 isoforms alpha and beta have unique and specific functions. Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, Murray-Tait V, Chiarle R, Poli V Nat Immunol 2004; 5: 401-409. Medline 15021879

Activation of the STAT Pathway in Acute Lung Injury. Severgnini M, Takahashi S, Rozo LM, Homer RJ, Kuhn C, Jhung JW, Perides G, Steer M, Hassoun PM, Fanburg BL, Cochran BH,Simon AR. Am J Physiol Lung Cell Mol Physiol 2004 Medline 14729509

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Brent H Cochran 2004 Citation This paper should be referenced as such : Cochran BH . STAT3 (Signal Transducer and Activator of Transcription 3). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/STAT3ID444.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -406- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TFE3 (transcription factor E3) (updated: old version not available)

Identity Hugo TFE3 Location Xp11.2 DNA/RNA

Description 8 exons Transcription differential splicing removing exon 3 (with dominant negative activity of the resulting protein) Protein

Description 743 amino acids; 80 kDa; N-term acidic transcriptional activation domain (domain 260-271, exon 3), helix-loop-helix (344 -400), leucine zipper (409-430), and a proline/arginine rich sequence (575-743) C-term Expression wide; in fetal and adult tissues Localisation nucleus Function transcription factor; member of the basic helix-loop-helix family (b-HLH) of transcription factors primarily found to bind to the immunoglobulin enchancer muE3 motif, Ig K enhancers and Ig H variable regions promotors; the helix-loop-helix - leucine zipper region is implicated in DNA binding and dimerization (homo and heterodimerizations); mice which lack TFE3 in their B and T lymphocytes reconstitute the B- and T- cell compartments, but IgM levels are reduced Homology to other members of the myc family of helix-loop-helix transcription factors Implicated in Entity t(X;1)(p11.2;q21.2) in renal cell carcinoma --> PRCC/TFE3

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -407- Prognosis overall 5-yr survival rate around 85% Hybrid/Mutated 5' PRCC- 3' TFE3; variable breakpoint in PRCC; breakpoint in the Gene 1st intron of TFE3 Abnormal N-term PRCC with the proline rich sequence fused to most of TFE3, Protein including the acidic transcriptional activation domain, the helix-loop- helix, and the leucine zipper; the reciprocal TFE3-PRCC is expressed; it is to be noted that the normal TFE3 transcript is lost in female patients

Oncogenesis PRCCTFE3 appears to be the fusion product that is most critical for the development of papillary renal cell carcinomas; it is a three-fold better transactivator than wild-type TFE3 and shows the characteristics associated with malignant trannsformation

Entity t(X;1)(p11.2;p34) in renal cell carcinoma --> PSF/TFE3 Disease t(X;1)(p11.2;p34) has only been found in a handfull cases of papillary renal cell carcinoma

Hybrid/Mutated 5' PSF- 3' TFE3 Gene Abnormal N-term PSF and most of it fused to the DNA binding domains of Protein TFE3 (excluding the acidic transcriptional activation domain, including the C-term helix-loop-helix, and the leucine zipper); no TFE3-PSF reciprocal transcript, as the der(X) t(X;1) is missing; the normal TFE3 transcript is found

Entity inv(X)(p11.2q12) in renal cell carcinoma --> NonO/TFE3 Disease only one case of papillary renal cell carcinoma

Hybrid/Mutated 5' NONO- 3' TFE3 Gene Abnormal N-term NONO and most of it except the C-term proline rich sequence

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -408- Protein fused to the DNA binding domains of TFE3 (excluding the acidic transcriptional activation domain, including the C-term helix-loop- helix, and the leucine zipper); the reciprocal transcript is found

Entity Alveolar soft part sarcoma with ASPSCR1 -TFE3 fusion Cytogenetics der(X)t(X;17)(p11;q25) is consistently involved; it implicates: 1- the formation of a hybrid gene at the breakpoint, and also, 2- gain in Xp11-pter sequences, and loss of heterozygocity in 11q25-qter, with possible implications Hybrid/Mutated 5' ASPSCR1-3' TFE3; the reciprocal 5' TFE3 - 3' ASPSCR1 is most Gene often absent. ASPSCR1 is fused in frame to TFE3 exon 3 or 4 Abnormal NH2 term ASPSCR1, fused to the C term of TFE3 Protein Oncogenesis might combine the effect of a fusion protein to that of gene(s) dosage

Entity primary renal ASPSCR1-TFE3 tumour Disease a subset of renal cell carcinoma, which presents with a combination of alveolar soft part sarcoma-like features and epithelial features is found to carry this anomaly Cytogenetics balanced t(X;17)(p11.2;q25), in contrast with what is found in the alveolar soft part sarcoma (see above) Hybrid/Mutated 5' ASPSCR1-3' TFE3 Gene Abnormal NH2 term ASPSCR1, fused to the C term of TFE3 Protein

Entity other Xp11 involvements in renal cell carcinoma (t(X;10)(p11;q23), etc ...) are likely to implicate TFE3

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -409- External links Nomenclature Hugo TFE3 GDB TFE3 Entrez_Gene TFE3 7030 transcription factor binding to IGHM enhancer 3 Cards Atlas TFE3ID86 GeneCards TFE3 Ensembl TFE3 CancerGene TFE3 Genatlas TFE3 GeneLynx TFE3 eGenome TFE3 euGene 7030 Genomic and cartography TFE3 - Xp11.2 chrX:48642490-48657239 - Xp11.23 (hg17- GoldenPath May_2004) Ensembl TFE3 - Xp11.23 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TFE3 Gene and transcription

Genbank X97160 [ SRS ] X97160 [ ENTREZ ]

Genbank X99721 [ SRS ] X99721 [ ENTREZ ]

Genbank AL161985 [ SRS ] AL161985 [ ENTREZ ]

Genbank BC001532 [ SRS ] BC001532 [ ENTREZ ]

Genbank BC026027 [ SRS ] BC026027 [ ENTREZ ]

RefSeq NM_006521 [ SRS ] NM_006521 [ ENTREZ ]

RefSeq NT_086942 [ SRS ] NT_086942 [ ENTREZ ] AceView TFE3 AceView - NCBI TRASER TFE3 Traser - Stanford

Unigene Hs.274184 [ SRS ] Hs.274184 [ NCBI ] HS274184 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P19532 [ SRS] P19532 [ EXPASY ] P19532 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ] CluSTr P19532

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -410- Blocks P19532 Polymorphism : SNP, mutations, diseases OMIM 314310 [ map ] GENECLINICS 314310

SNP TFE3 [dbSNP-NCBI]

SNP NM_006521 [SNP-NCI]

SNP TFE3 [GeneSNPs - Utah] TFE3 [SNP - CSHL] TFE3] [HGBASE - SRS] General knowledge Family TFE3 [UCSC Family Browser] Browser SOURCE NM_006521 SMD Hs.274184 SAGE Hs.274184 Amigo function|ATP binding Amigo function|catalytic activity Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|tRNA aminoacylation for protein translation Amigo function|tRNA ligase activity Amigo function|transcription factor activity Amigo process|transcription from Pol II promoter PubGene TFE3 Other databases Probes Probe TFE3 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Beckmann H, Su LK, Kadesch T Genes Dev 1990 Feb;4(2):167-79 Medline 90249724

The leucine zipper of TFE3 dictates helix-loop-helix dimerization specificity Beckmann H, Kadesch T Genes Dev 1991 Jun;5(6):1057-66 Medline 91257572

A dominant negative form of transcription activator mTFE3 created by

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -411- differential splicing. Roman C, Cohn L, Calame K Science 1991 Oct 4;254(5028):94-7 Medline 92022552

Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Weterman MA, Wilbrink M, Geurts van Kessel A. Proc Natl Acad Sci USA 1996; 93: 15294-15298. Medline 8986805

The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS Hum Mol Genet 1996 Sep;5(9):1333-8 Medline 97026295

Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS Oncogene 1997 Oct;15(18):2233-9 Medline 98054131

The absence of the transcription activator TFE3 impairs activation of B cells in vivo. Merrell K, Wells S, Henderson A, Gorman J, Alt F, Stall A, Calame K Mol Cell Biol 1997 Jun;17(6):3335-44 Medline 97299683

Nuclear localization and transactivating capacities of the papillary renal cell carcinoma-associated TFE3 and PRCC (fusion) proteins. Weterman MJ, van Groningen JJ, Jansen A, van Kessel AG. Oncogene 2000; 19: 69-74. Medline 10644981

The der(17)t(X.17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PHB, Mertens F, Mandahl N, van den Berghe H, Sciot R, dal Cin P, Bridge J. Oncogene 2001; 20: 48-57. Medline 21140288

Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -412- sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. Am J Pathol 2001; 159: 179-192. Medline 21331068

Transformation capacities of the papillary renal cell carcinoma-associated PRCCTFE3 and TFE3PRCC fusion genes. Weterman MA, van Groningen JJ, den Hartog A, Geurts van Kessel A. Oncogene 2001; 20: 1414-1424. Medline 11313885

Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)- bearing papillary renal cell carcinomas. Heimann P, El Housni H, Ogur G, Weterman MA, Petty EM, Vassart G. Cancer Res 2001; 61: 4130-4135. Medline 11358836

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Jean-Loup Huret and François Desangles 1999 Updated 08- Jean-Loup Huret 2001 Updated 05- Roland P Kuiper 2004 Citation This paper should be referenced as such : Huret JL and Desangles F . TFE3 (transcription factor E3). Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFE3ID86.html Kuiper RP . TFE3 (transcription factor E3). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFE3ID86.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -413- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TFEB (transcription factor EB)

Identity Note Member of the basic-helix-loop-helix leucine-zipper transcription factor MiTF/TFE family (also known as the MiT family), which also contains MiTF, TFEC, and TFE3. The four members form homo- and/or heterodimers to bind the Ebox core sequence CAYGTG. Other T-cell Transcription Factor EB, TCFEB names Hugo TFEB Location 6p21 DNA/RNA

Genomic organization of TFEB gene.

Description TFEB gene contains 8 coding exons and 7 alternative first exons that are differentially expressed. Transcription Alternative first exon usage points towards the existence of up to seven alternative promoters. Alternative splicing of exon 3 (encoding an acidic activation domain) similar to the closely related TFE3, TFEC, and MiTF genes. Protein

Functional domains in the TFEB protein.

Description 490 amino acids; 65 kDa; N-terminal Gln-rich stretch (Gln, exon 2), N- term acidic transcriptional activation domain (AAD, exon 3), basic helix- loop-helix region (bHLH, exon 6-8), leucine zipper (LZ, exon 8), proline- rich activation domain ( ProAD, exon 9), Ser-rich stretch (Ser) Expression Wide in fetal and adult tissues, although the various TFEB transcript variants are expressed in a tissue-restricted manner: TFEB-A is

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -414- enriched in placenta, TFEB-F in spleen, and TFEB-E and TFEB-G in brain. Localisation Nucleus Function Transcription factor; member of the basic-helix-loop-helix leucine-zipper transcription factor MiTF/TFE family (also known as the MiT family), which also contains MiTF, TFEC, and TFE3. The four members form homo- and/or heterodimers to bind the Ebox core sequence CAYGTG; the helix-loop-helix - leucine zipper region is implicated in DNA binding and dimerization (homo and heterodimerizations); mice which lack TFEB die due to defects in placental vascularization. Homology High homology to the other MiTF/TFE members TFE3, TFEC and MiTF, homologous to myc family of bHLH transcription factors. Implicated in Entity Renal cell carcinoma with t(6;11)(p21;q13) -> Alpha/TFEB gene fusion Disease Clear cell renal cell carcinomas Prognosis Limited follow-up available, prognosis appears to be good; no reports of developed metastases Cytogenetics t(6;11)(p21;q13), usually as the sole cytogenetic anomaly. Hybrid/Mutated Alpha/TFEB, both fusion genes are expressed; 5'-Alpha-TFEB-3' Gene fusion transcript contains the entire open reading frame of TFEB. Abnormal No fusion protein, the Alpha gene is a non-protein-encoding Protein transcript. Oncogenesis Highly induced expression of full-length TFEB protein due to promoter substitution in the Alpha-TFEB fusion gene.

External links Nomenclature Hugo TFEB GDB TFEB Entrez_Gene TFEB 7942 transcription factor EB Cards Atlas TFEBID531 GeneCards TFEB Ensembl TFEB CancerGene TFEB Genatlas TFEB GeneLynx TFEB eGenome TFEB euGene 7942

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -415- Genomic and cartography TFEB - 6p21 chr6:41759695-41810776 - 6p21.1 (hg17- GoldenPath May_2004) Ensembl TFEB - 6p21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TFEB Gene and transcription

Genbank AJ535461 [ SRS ] AJ535461 [ ENTREZ ]

Genbank AL035588 [ SRS ] AL035588 [ ENTREZ ]

Genbank AJ608786 [ SRS ] AJ608786 [ ENTREZ ]

Genbank AJ608787 [ SRS ] AJ608787 [ ENTREZ ]

Genbank AJ608788 [ SRS ] AJ608788 [ ENTREZ ]

RefSeq NM_007162 [ SRS ] NM_007162 [ ENTREZ ]

RefSeq NT_086693 [ SRS ] NT_086693 [ ENTREZ ] AceView TFEB AceView - NCBI TRASER TFEB Traser - Stanford

Unigene Hs.485360 [ SRS ] Hs.485360 [ NCBI ] HS485360 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P19484 [ SRS] P19484 [ EXPASY ] P19484 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR009065 FERM [ SRS ] IPR009065 FERM [ EBI ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ] CluSTr P19484

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ]

Smart SM00353 HLH [EMBL] Blocks P19484 Polymorphism : SNP, mutations, diseases OMIM 600744 [ map ] GENECLINICS 600744

SNP TFEB [dbSNP-NCBI]

SNP NM_007162 [SNP-NCI]

SNP TFEB [GeneSNPs - Utah] TFEB [SNP - CSHL] TFEB] [HGBASE - SRS] General knowledge Family TFEB [UCSC Family Browser] Browser SOURCE NM_007162 SMD Hs.485360

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -416- SAGE Hs.485360 Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity PubGene TFEB Other databases Probes Probe TFEB Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography A helix-loop-helix protein related to the immunoglobulin E box-binding proteins. Carr CS., Sharp PA. Mol Cell Biol 1990; 10: 4384-4388. Medline 2115126

TFEB has DNA-binding and oligomerization properties of a unique helix- loop- helix/leucine-zipper family. Fisher DE, Carr CS, Parent LA, Sharp PA. Genes Dev 1991; 5: 2342-2352. Medline 1748288 microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Hemesath TJ, Steingrimsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, Arnheiter H, Copeland NG, Jenkins NA, Fisher DE Genes Dev 1994; 8: 2770-2780. Medline 7958932

The bHLH-Zip transcription factor Tfeb is essential for placental vascularization. Steingrimsson E, Tessarollo L, Reid SW, Jenkins NA, Copeland NG Development 1998; 125: 4607-4616. Medline 9806910

A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. Argani P, Hawkins A, Griffin CA, Goldstein JD, Haas M, Beckwith JB, Mankinen CB, Perlman EJ. Am J Pathol 2001; 158: 2089-2096. Medline 11395386

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -417- Recent advances in pediatric renal neoplasia. Argani P, Ladanyi M. Adv Anat Pathol 2003; 10: 243-260 (REVIEW). Medline 12973047

Distinctive neoplasms characterised by specific chromosomal translocations comprise a significant proportion of paediatric renal cell carcinomas. Argani P, Ladanyi M. Pathology 2003; 35: 492-498 (REVIEW). Medline 14660099

Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Davis IJ, His BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez- Atayde AR, Argani P, Ladanyi M. Fletcher JA, Fisher DE. Proc Natl Acad Sci USA 2003; 100: 6051-6056. Medline 12719541

Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers HFPM and Geurts van Kessel A. Hum Mol Genet 2003; 12: 1661-1669. Medline 12837690

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Roland P Kuiper 2004 Citation This paper should be referenced as such : Kuiper RP . TFEB (transcription factor EB). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFEBID531.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -418- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CHFR (Checkpoint with fork-head associated and ring finger)

Identity Note CHFR functions as part of an early G2/M checkpoint. This putative early mitotic checkpoint causes a delay in chromosome condensation in response to mitotic stress. Human CHFR gene was originally identified during a search for novel cell cycle checkpoint proteins that have fork- head associated domains. Initial analysis indicated that the CHFR- associated G2/M checkpoint was inactivated in a subset of cancers as demonstrated by high mitotic indices (a high percentage of cells that have condensed chromosomes) in response to exposure to the microtubule poison, nocodazole, due to lack of CHFR expression or CHFR mutations in a neuroblastoma, an osteosarcoma and 2 colon cancer cell lines (4 of 8 different cancer cell lines). Further studies demonstrated loss of or low CHFR expression in various types of cancer cells including those from colon, esophageal, gastric, lung and breast cancers. Other FLJ10796 names Hugo CHFR Location 12q24.33 Genes flanking CHFR in centromere to telomere direction on 12q24.33: Peroxisomal membrane protein 2 gene (PXMP2) Hypothetical protein gene (MGC5352) Golgi autoantigen, golgin subfamily a3 gene (GOLGA3) Checkpoint with FHA and RING finger gene (CHFR) Hypothetical gene (GeneID: 90462) Zinc finger protein 26 gene (ZNF26) DNA/RNA Description The CHFR gene spans approximately 47 kb and has at least 18 exons (BC012072 vs. NT_024477) as predicted according to Spidey (http://www.ncbi.nlm.nih.gov/spidey/) but experimental confirmation of the genomic structure has not been reported. Transcription CHFR mRNA is 3189 bp (BC012072). Transcripts that lack exon 2, exon 5 and exon 6 have been detected in various tissues including bone marrow, small intestine, lung, heart, testis, kidney, stomach and lympocytes as well as some cancer cell lines by RT-PCR. In silico hypothetical alternatively spliced transcripts that have not yet been experimentally demonstrated can be also found at AceView. Northern

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -419- blot transcript analysis suggests that limited if any alternative splicing is present in most fetal and adult tissues where CHFR is expressed a prominent 3.2 kb is observed. CHFR mRNA is detected in heart, brain, placenta, lung, liver, muscle, kidney, pancreas by Northern blot analysis. Protein

Description CHFR encodes a 652 amino acid protein (according to BC012072 nucleotide sequence) with FHA (forkhead associated), RING (really interesting new gene) finger and cysteine rich domains. No alternative isoforms have been described to date.

Domains:

FHA domains are present in cell cycle checkpoint genes, transcription factors, protein kinases and have roles in protein-protein interactions with specificity for phosphorylated targets. The three dimensional structure of CHFR suggests that CHFR may be able to recognize as of yet unidentified phosphorylated targets. RING finger domains are found in ubiquitin ligases. Ubiquitin ligases attach ubiquitin to target proteins during a cascade of enzymatic reactions. RING finger domains are present in a variety of proteins (e.g. Anaphase promoting complex, APC, Cbl family proteins, MDM2) implicated in cancer. Function CHFR induces an early G2/M checkpoint in response to mitotic stress. Cell lines expressing wild-type CHFR exhibit low mitotic index (percentage of cells with condensed chromosomes) and delayed entry into metaphase when centrosome separation is inhibited by mitotic stress. In contrast, cancer cell lines lacking CHFR function enter metaphase without delay and demonstrate higher mitotic indices compared to the CHFR expressing cell lines.

In vitro studies suggest that the RING finger domain in CHFR also facilitates ubiquitin ligase function and that it is essential for checkpoint function of CHFR. In vitro Xenopus extract experiments suggested that CHFR specifically targets PLK1 (polo-like kinase 1) for degradation when extracts are supplemented with high ubiquitin concentrations. Thus, according to this in vitro model, CHFR is able to halt cell cycle progression early in mitosis by degrading PLK1, a major player for the activation of mitosis promoting factor.

However, a more recent study suggests that the ubiquitin ligase function of CHFR may be different than the current in vitro model and that instead of Lys48 ubiquitination, CHFR may link ubiquitin to target protein or proteins via Ly63 due to its interaction with the heteromeric ubiquitin conjugating enzyme complex, Ubc13-Mms2. In the canonical ubiquitin/proteasome pathway, Lys48 is a signal for degradation of target proteins whereas Lys63 ubiquitination functions as a non-

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -420- proteolytic tag for protein targets. The mechanistic roles of Lys63 are not understood but this type of ubiquitination is involved in error-free post-replicative DNA repair and NF-kB signal transduction. Homology M.musculus 5730484M20Rik RIKEN cDNA 5730484M20 gene, R.norvegicus LOC288734 similar to RIKEN cDNA 5730484M20, budding yeast proteins, Dma1 and Dma2 are 58% identical to each other and are possible homologs of human CHFR. Dma1 and Dma2 have roles in spindle formation and formation of septin ring during cytokinesis. Mutations Germinal No germline mutations have been reported yet. Somatic A panel of 53 lung carcinomas has been screened with matching normal tissue and 3 mutations were found, one of which was associated with loss of heterozygosity. Mutations found in patient samples were: C587T, G695C (both between the FHA and RING domains) and T1697C (in the C-terminal cysteine rich region of CHFR). However, no correlation was found with a specific diagnosis or stage of the disease in the patients. Implicated in Disease Lack or decreased expression of CHFR is observed in a variety of cancer cell lines and tumors. Hypermethylation of the CHFR promoter is detected in a variety of cancer cell lines including esophageal, colon, lung, osteosarcoma, central nervous system, leukemic and primary tumors of the colon, lung and esophagus suggesting that decrease or loss of expression is associated with the hypermethylation of CHFR promoter. Primary cancers of various origin (11 of 30 (37%) colon adenocarcinomas, 2 of 20 (10%) primary non-small lung carcinomas, 7 of 37 (19%) lung cancer specimens, 25 of 63 (40%) primary colorectal cancers, 27 of 51 (53%) colorectal adenomas, 16 of 54 (30%) head and neck cancers also demonstrate hypermethylation of CHFR promoter. CpG methylation and silencing of CHFR depends on the activities of two DNA methyltransferases, DNMT1 and DNMT3b since their inactivation restores CHFR expression. Cytogenetics A lung cancer patient sample demonstrates loss of heterozygosity for a CA repeat located on a BAC that contains the CHFR gene. Several other cancers demonstrate allelic imbalance involving chromosome band 12q24 but specific analysis of CHFR in these samples has not been investigated. Abnormal None described Protein Oncogenesis A wide variety of cancer cell lines and tumor samples demonstrate lack of or low CHFR expression associated with abnormal checkpoint responses after treatment with nocodazole. Currently it is unclear which in vivo events trigger activation of the CHFR-associated G2/M checkpoint and which proteins interact with or regulate CHFR. The fact that nocodazole is a microtubule depolymerizing agent that can activate the checkpoint before the formation of microtubule spindles

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -421- suggests that early events dependent on microtubules such as centrosome duplication and separation may be monitored by this checkpoint.

External links Nomenclature Hugo CHFR GDB CHFR Entrez_Gene CHFR 55743 checkpoint with forkhead and ring finger domains Cards Atlas CHFRID526 GeneCards CHFR Ensembl CHFR CancerGene CHFR Genatlas CHFR GeneLynx CHFR eGenome CHFR euGene 55743 Genomic and cartography CHFR - 12q24.33 chr12:132027288-132074534 - 12q24.33 GoldenPath (hg17-May_2004) Ensembl CHFR - 12q24.33 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CHFR Gene and transcription

Genbank AF170724 [ SRS ] AF170724 [ ENTREZ ]

Genbank AK001658 [ SRS ] AK001658 [ ENTREZ ]

Genbank AK027687 [ SRS ] AK027687 [ ENTREZ ]

Genbank AK054917 [ SRS ] AK054917 [ ENTREZ ]

Genbank AK097671 [ SRS ] AK097671 [ ENTREZ ]

RefSeq NM_018223 [ SRS ] NM_018223 [ ENTREZ ]

RefSeq NT_086797 [ SRS ] NT_086797 [ ENTREZ ] AceView CHFR AceView - NCBI TRASER CHFR Traser - Stanford

Unigene Hs.507336 [ SRS ] Hs.507336 [ NCBI ] HS507336 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -422- OMIM 605209 [ map ] GENECLINICS 605209

SNP CHFR [dbSNP-NCBI]

SNP NM_018223 [SNP-NCI]

SNP CHFR [GeneSNPs - Utah] CHFR [SNP - CSHL] CHFR] [HGBASE - SRS] General knowledge Family CHFR [UCSC Family Browser] Browser SOURCE NM_018223 SMD Hs.507336 SAGE Hs.507336 PubGene CHFR Other databases Probes Probe CHFR Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Conducting the mitotic symphony. Cortez D, Elledge SJ. Nature 2000; 406: 354-356. Medline 10935617

Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Scolnick DM, Halazonetis TD. Nature 2000; 406: 430-435. Medline 10935642

Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. Chaturvedi P, Sudakin V, Bobiak ML, Fisher PW, Mattern MR, Jablonski SA, Hurle MR, Zhu Y, Yen TJ, Zhou BB. Cancer Res 2002; 62: 1797-1801. Medline 11912157

The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. Kang D, Chen J, Wong J, Fang G. J Cell Biol 2002: 156: 249-259. Medline 11807090

Aberrant hypermethylation of the CHFR prophase checkpoint gene in human

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -423- lung cancers. Mizuno K, Osada H, Konishi H, Tatematsu Y, Yatabe Y, Mitsudomi T, Fujii Y, Takahashi T. Oncogene 2002; 21:2328-2333. Medline 11948416

Chfr expression is downregulated by CpG island hypermethylation in esophageal cancer. Shibata Y, Haruki N, Kuwabara Y, Ishiguro H, Shinoda N, Sato A, Kimura M, Koyama H, Toyama T, Nishiwaki T, Kudo J, Terashita Y, Konishi S, Sugiura H, Fujii Y. Carcinogenesis 2002;23:1695-1699. Medline 12376479

Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate. Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP, Jeffrey PD. Structure (Camb) 2002; 10: 891-899. Medline 12121644

FHA: a signal transduction domain with diverse specificity and function. Tsai MD. Structure (Camb) 2002; 10: 887-888. Medline 12121642

Chfr inactivation is not associated to chromosomal instability in colon cancers. Bertholon J, Wang Q, Falette N, Verny C, Auclair J, Chassot C, Navarro C, Saurin JC, Puisieux A. Oncogene 2003; 22: 8956-8960. Medline 14654793

The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63- linked polyubiquitin chains. Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD. Oncogene. 2003 Oct 16; 22: 7101-7107. Medline 14562038

Frequent hypermethylation of the 5' CpG island of the mitotic stress checkpoint gene Chfr in colorectal and non-small cell lung cancer. Corn PG, Summers MK, Fogt F, Virmani AK, Gazdar AF, Halazonetis TD, El-Deiry WS. Carcinogenesis 2003; 24: 47-51. Medline 12538348

Inactivating mutations targeting the chfr mitotic checkpoint gene in human lung cancer.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -424- Mariatos G, Bothos J, Zacharatos P, Summers MK, Scolnick DM, Kittas C, Halazonetis TD, Gorgoulis VG. Cancer Res 2003; 63:7185-7189. Medline 14612512

Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K, Kikuchi T, Mita H, Yamashita T, Kojima T, Kusano M, Fujita M, Hosokawa M, Endo T, Tokino T, Imai K. Cancer Res 2003; 63: 8606-8613. Medline 14695171

Promotion of mitosis by activated protein kinase B after DNA damage involves polo-like kinase 1 and checkpoint protein CHFR. Shtivelman E. Mol Cancer Res. 2003 Nov;1(13):959-969. Medline 14638868

Epigenetic inactivation of CHFR in human tumors. Toyota M, Sasaki Y, Satoh A, Ogi K, Kikuchi T, Suzuki H, Mita H, Tanaka N, Itoh F, Issa JP, Jair KW, Schuebel KE, Imai K, Tokino T. Proc Natl Acad Sci U S A 2003; 100: 7818-7823. Medline 12810945

CHFR-associated early G2/M checkpoint defects in breast cancer cells. Erson AE, Petty EM. Mol Carcinog 2004; 39: 26-33. Medline 14694445

Functional characterization of Dma1 and Dma2, the budding yeast homologues of S. pombe Dma1 and human Chfr. Fraschini R, Bilotta D, Lucchini G, Piatti S. Mol Biol Cell. 2004 May 14 [Epub ahead of print] Medline 15146058

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

BiblioGene - INIST

Contributor(s) Written 06- Ayse E Erson, Elizabeth M Petty 2004

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -425- Citation This paper should be referenced as such : Erson AE, Petty EM . CHFR (Checkpoint with fork-head associated and ring finger). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CHFRID526.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -426- Atlas of Genetics and Cytogenetics in Oncology and Haematology

DIRC1

Identity Location 2q33 DNA/RNA Description The DIRC1 gene contains 2 exons and spans approximately 57 kb of genomic DNA. Protein

Description 104 amino acids Expression Expression in adult placenta, testis, ovary, prostate, and in fetal kidney, spleen, and skeletal muscle. Function unknown Implicated in Entity t(2;3)(q33;q21) in hereditary renal cell cancer. Disease Familial renal cell cancer. Cytogenetics Disruption of the gene because of the t(2;3) translocation.

External links Nomenclature GDB DIRC1 Entrez_Gene DIRC1 116093 disrupted in renal carcinoma 1 Cards Atlas DIRC1ID499 GeneCards DIRC1 Ensembl DIRC1 CancerGene DIRC1 Genatlas DIRC1 GeneLynx DIRC1 eGenome DIRC1 euGene 116093 Genomic and cartography GoldenPath DIRC1 - 2q33 chr2:189423971-189480337 - 2q32.2 (hg17-

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -427- May_2004) Ensembl DIRC1 - 2q32.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene DIRC1 Gene and transcription

Genbank AY039013 [ SRS ] AY039013 [ ENTREZ ]

Genbank AY039011 [ SRS ] AY039011 [ ENTREZ ]

RefSeq NM_052952 [ SRS ] NM_052952 [ ENTREZ ]

RefSeq NT_086633 [ SRS ] NT_086633 [ ENTREZ ] AceView DIRC1 AceView - NCBI TRASER DIRC1 Traser - Stanford

Unigene Hs.470892 [ SRS ] Hs.470892 [ NCBI ] HS470892 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q969H9 [ SRS] Q969H9 [ EXPASY ] Q969H9 [ INTERPRO ] CluSTr Q969H9 Blocks Q969H9 Polymorphism : SNP, mutations, diseases OMIM 606423 [ map ] GENECLINICS 606423

SNP DIRC1 [dbSNP-NCBI]

SNP NM_052952 [SNP-NCI]

SNP DIRC1 [GeneSNPs - Utah] DIRC1 [SNP - CSHL] DIRC1] [HGBASE - SRS] General knowledge Family DIRC1 [UCSC Family Browser] Browser SOURCE NM_052952 SMD Hs.470892 SAGE Hs.470892 PubGene DIRC1 Other databases Probes PubMed PubMed 1 Pubmed reference(s) in LocusLink Bibliography The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. Druck T, Podolski J, Byrski T, Wyrwicz L, Zajaczek S, Kata G, Borowka A, Lubinski J, Huebner K.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -428- J Hum Genet 2001; 46(10): 583-589. Medline 11587072

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB, Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K. J Hum Genet 2001; 46(12): 685-693. Medline 11776380

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Anita Bonné, Eric Schoenmakers, Ad Geurts van Kessel. 2004 Citation This paper should be referenced as such : Bonné A, Schoenmakers E, Geurts van Kessel A. . DIRC1. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/DIRC1ID499.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -429- Atlas of Genetics and Cytogenetics in Oncology and Haematology

FGA7 (Fused Gene 7 to AML1)

Identity Location 4q28

Metaphase FISH analysis using the BAC probe RP11-104M2 labeled with FITC (green) hybridized to a normal metaphase cell confirms the chromosomal localization of the probe (gene) to 4q28.

DNA/RNA Description The gene has not been fully cloned at the present time. A 476-base novel sequence fused to AML1 has been identified and sequenced as a result of the molecular cloning of the t(4;21)(q28;q22). The novel sequence maps to chromosome band 4q28. Sequence analysis did not show any significant homology with any of the known genes in the human GenBank DNA database. However the first 118-bases are identical to a part of human ovarian EST-11116119. Also, the first 196- bases of the sequence show 87% homology with a mouse sequence, whereas the first 237-bases show 85% homology with a rat sequence. Based on the high degree of identity among the three species, it is very likely that the novel sequence represents a part of a novel gene, which was named FGA7.

FGA7 sequence is contained within three human genomic BAC clones: RP11-104M2, RP11-153C5, and RP11-595L6.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -430- t(4;21)(q28;q22) generates two fusion transcripts due to alternative splicing of AML1. Transcript I contains AML1 exon 5 fused to FGA7, whereas transcript II contains AML1 exon 6 fused to FGA7. Protein

Description AML1-FGA7 fusion encodes two variant chimeric proteins, both of which consist of the N-terminus of AML1 including the RUNT domain, but differ in the inclusion of AML1 exon 6. Both predicted proteins contain an identical C-terminus derived from FGA7 that adds 27 amino acids after the AML1 breakpoint. Expression FGA7 is not expressed in normal hematopoietic tissue. It is expressed in skeletal muscle and ovarian tissues with a transcript size of about 11kb. Homology FGA7 shows high homology to mouse and rat sequences. Implicated in Entity t(4;21)(q28;q22) leading to AML1-FGA7 gene fusion Disease Pediatric T-cell ALL. Prognosis Poor. Cytogenetics Associated with del(7)(q22).

Schematic representation of AML1 and AML1-FGA7 fusion transcripts. Top, diagram of AML1 shows the RUNT domain (RD) and the transactivation domain (TA) separated by exon 6. Center, the fusion of AML1 exon 6 to FGA7 results in the addition of 27 codons. The asterisks indicate the stop codon. Bottom, the alternative splice form that does not include exon 6 is shown.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -431-

Metaphase FISH analysis using the BAC probe RP11-104M2 hybridized to the patient's metaphase shows one normal green signal on the intact chromosome 4 (dashed arrow) and two smaller green signals on der(21) (arrowhead) and on der(4) (arrow) as a result of the t(4;21)(q28;q22). Oncogenesis The predicted AML1-FGA7 chimeric proteins contain a limited number of amino acid residues fused to AML1 in a situation similar to that reported for AML1-EAP fusion that is a product of t(3;21). It is possible that the expression of a constitutively shortened AML1 could compete with full-length AML1 and act as a dominant negative inhibitor of the promoters that the core binding factor (CBF) activates.

External links Nomenclature Cards Genomic and cartography Gene and transcription Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases General knowledge Other databases Probes PubMed Bibliography A new translocation that rearranges the AML1 gene in a patient with T-cell acute lymphoblastic leukemia. Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Coignet L, Nucifora G. Cancer Genet Cytogenet 2002; 135(1): 96-100. Medline 12072207

A novel gene, FGA7, is fused to RUNX1/AML1 in a t(4;21)(q28;q22) in a patient with T-cell acute lymphoblastic leukemia. Mikhail FM, Coignet L, Hatem N, Mourad ZI, Farawela HM, El Kaffash DM, Farahat N, Nucifora G.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -432- Genes Chromosomes Cancer 2004; 39(2): 110-118. Medline 14695990

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Fady M Mikhail, Giuseppina Nucifora 2004 Citation This paper should be referenced as such : Mikhail FM, Nucifora G . FGA7 (Fused Gene 7 to AML1). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FGA7ID525.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -433- Atlas of Genetics and Cytogenetics in Oncology and Haematology

HSPBAP1 (HSPB (heat shock 27kDa) associated protein 1)

Identity Other PASS1 names FLJ22623 3_123833568 Hugo HSPBAP1 Location 3q21.1 DNA/RNA Description The HSPBAP1 gene covers 54.67 kb. The gene contains 13 confirmed introns, 12 of which are alternative. In the t(2;3)(q35;q21) translocation, HSPBAP1 was found to be fused to DIRC3. Protein

Description 488 amino acids Localisation Plasma membrane Function The protein encodes a set of transcription factor jumonji, jmjC family members. The Transcription factor jumonji, jmjC motif, is found in 2 isoforms from this gene. Jumonji protein is required for neural tube formation in mice.There is evidence of domain swapping within the jumonji family of transcription factors. This domain is often associated with jmjN. Implicated in Entity t(2;3)(q35;q21) and hereditary renal cell cancer. Disease Familial renal cell cancer Cytogenetics Disruption of the gene because of the t(2;3) translocation. Hybrid/Mutated DIRC3/HSPBAP1 Gene

External links Nomenclature Hugo HSPBAP1 GDB HSPBAP1

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -434- Entrez_Gene HSPBAP1 79663 HSPB (heat shock 27kDa) associated protein 1 Cards Atlas HSPBAP1ID513 GeneCards HSPBAP1 Ensembl HSPBAP1 Genatlas HSPBAP1 GeneLynx HSPBAP1 eGenome HSPBAP1 euGene 79663 Genomic and cartography HSPBAP1 - 3q21.1 chr3:123941536-123995340 - 3q21.1 GoldenPath (hg17-May_2004) Ensembl HSPBAP1 - 3q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene HSPBAP1 Gene and transcription

Genbank AF400663 [ SRS ] AF400663 [ ENTREZ ]

Genbank AK026276 [ SRS ] AK026276 [ ENTREZ ]

Genbank AK096705 [ SRS ] AK096705 [ ENTREZ ]

Genbank BC011897 [ SRS ] BC011897 [ ENTREZ ]

Genbank BC017763 [ SRS ] BC017763 [ ENTREZ ]

RefSeq NM_024610 [ SRS ] NM_024610 [ ENTREZ ]

RefSeq NT_086640 [ SRS ] NT_086640 [ ENTREZ ] AceView HSPBAP1 AceView - NCBI TRASER HSPBAP1 Traser - Stanford

Unigene Hs.29169 [ SRS ] Hs.29169 [ NCBI ] HS29169 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q8NHH6 [ SRS] Q8NHH6 [ EXPASY ] Q8NHH6 [ INTERPRO ]

Interpro IPR007113 Cupin_region [ SRS ] IPR007113 Cupin_region [ EBI ]

Interpro IPR003347 TF_JmjC [ SRS ] IPR003347 TF_JmjC [ EBI ] CluSTr Q8NHH6

Pfam PF02373 JmjC [ SRS ] PF02373 JmjC [ Sanger ] pfam02373 [ NCBI-CDD ]

Smart SM00558 JmjC [EMBL] Blocks Q8NHH6 Polymorphism : SNP, mutations, diseases OMIM 608263 [ map ] GENECLINICS 608263

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -435- SNP HSPBAP1 [dbSNP-NCBI]

SNP NM_024610 [SNP-NCI]

SNP HSPBAP1 [GeneSNPs - Utah] HSPBAP1 [SNP - CSHL] HSPBAP1] [HGBASE - SRS] General knowledge Family HSPBAP1 [UCSC Family Browser] Browser SOURCE NM_024610 SMD Hs.29169 SAGE Hs.29169 PubGene HSPBAP1 Other databases Probes Probe HSPBAP1 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Identification and characterization of a novel protein from Sertoli cells, PASS1, that associates with mammalian small stress protein hsp27. Liu C, Gilmont RR, Benndorf R, Welsh MJ. J Biol Chem 2000; 275(25): 18724-18731. Medline 10751411

Molecular cloning and characterization of a novel human gene (HSPBAP1) from human fetal brain. Jiang M, Ma Y, Cheng H, Ni X, Guo L, Xie Y, Mao Y. Cytogenet Cell Genet 2001; 95(1-2): 48-51. Medline 11978969

Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21). Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF, Geurts van Kessel A. Genes Chromosomes Cancer 2003; 38(2): 107-16. Medline 12939738

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -436- This paper should be referenced as such : Bonné A, Schoenmakers E, Geurts van Kessel A. . HSPBAP1 (HSPB (heat shock 27kDa) associated protein 1). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/HSPBAP1ID513.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -437- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NQO1 (updated: old version not available)

Identity Other DIA4 names DT-Diaphorase NMO1 Hugo NQO1 Location 16q22.1

NQO1 (16q22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description Spans approximately 20 kb consisting of 6 exons and 5 introns. Highly inducible protein and the 5' flanking region contains an AP2, ARE or EpRE(antioxidant or electrophile responsive element) and an XRE (xenobiotic responsive element). Transcription Three mRNA sizes (1.2, 1.7 and 2.7 kb) have been observed due to multiple polyadenylation sites. An alternatively spliced form of NQO1 mRNA lacking exon 4 is also possible although the corresponding truncated protein has not been detected. Protein

Description NQO1 is a flavoprotein which functions as a homodimer. The physiological dimer has one catalytic site per monomer. Each monomer consists of 273 amino acids. For structures of human recombinant NQO1 with quinones complexed in the active site see Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release (Structure Explorer - 1D4A) and. Structure-based development of antitumor quinones. Complexes of NQO1 with three potential chemotherapeutic quinones (Structure

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -438- Explorer - 1H66). Expression NQO1 is expressed in human epithelial and endothelial tissues and at high levels throughout many human solid tumors. Localisation NQO1 is a mainly cytosolic enzyme (approx. 90%) although it has also been localized in smaller amounts to mitochondria, endoplasmic reticulum and nucleus. Function NQO1 catalyzes obligate two electron reduction of a wide variety of substrates. The most efficient substrates are quinones but the enzyme will also reduce quinone-imines, nitro and azo compounds. The enzyme functions via a hydride transfer mechanism and requires a pyridine nucleotide cofactor. Reduction proceeds with equal facility with both NADH and NADPH. NQO1 can generate antioxidant forms of both vitamin E and ubiquinone after free radical attack. The capability to protect cells from oxidative challenge and the ability to reduce quinones via an obligate two electron mechanism, which precludes generation of reactive oxygen radicals, demonstrates that NQO1 is a chemoprotective enzyme. NQO1 knockout mice demonstrated increased susceptibility to benzo(a)pyrene and 7,12-dimethylbenz(a) anthracene induced skin carcinogenesis. NQO1 has been proposed to stabilize the tumor suppressor gene p53 and has been shown to interact with p53 in a protein-protein interaction.

Certain compounds such as antitumor quinones, however, can be bioactivated by two electron reduction and in these cases NQO1 serves as an activating enzyme. Because of the high levels of NQO1 in certain tumors, this has led to an interest in designing compounds which can be efficiently bioactivated by NQO1 as antitumor agents. Homology Amino acid homology across species is high (mouse/human 86%, mouse/rat -94%, human/rat 86%). NQO2 is a separate gene product demonstrating 49% and 54% similarity at the amino acid and nucleotide levels respectively. Mutations Germinal Two polymorphisms have been characterized. The NQO1 *2 allele represents a C609T change in the cDNA coding for a Pro187Ser change in the enzyme. The NQO1 *3 allele is a C465T change in the cDNA coding for an Arg139Trp change. The NQO1 * 2 allele is much more frequent than the *3 allele and has profound consequences for phenotype. The NQO1 *2 protein has diminished catalytic activity and the protein is rapidly degraded by the ubiquitin-proteasomal system. As a result, cells and tissues carrying the homozygous NQO1 *2 allele have no detectable NQO1 activity and at best, trace levels of NQO1 protein. The NQO1 *2/*2 genotype is effectively a null polymorphism. NQO1 is highly inducible and although NQO1 levels can vary considerably among individuals with the same genotype, the NQO1 *2 allele has been reported to show a gene dose effect since heterozygotes (NQO1 *1/*2) contained significantly less NQO1 protein than wild type (NQO1 *1/*1) samples.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -439- Implicated in Entity Leukemia Note Increased risk of leukemia has been associated with the NQO1 *2 allele and diminished NQO1 activity. Childhood leukemia (particularly with MLL fusions) , adult leukemia (ALL, AML particularly with translocations or inversions) and secondary leukemias and myelodysplasias as a result of chemotherapy have been associated with the NQO1 *2 polymorphism. Increased benzene induced myelotoxicity in occupationally exposed individuals has also been linked to the NQO1 *2 polymorphism.

Entity Solid tumors Note Increased risk of renal and urothelial cell carcinomas and cutaneous basal cell carcinomas have also been associated with the NQO1 *2 polymorphism but conflicting results have been obtained in colon cancer and lung cancer. A number of epidemiological studies have investigated the possible link between NQO1 and cancer and have been recently summarized [6].DISEASE

External links Nomenclature Hugo NQO1 GDB NQO1 Entrez_Gene NQO1 1728 NAD(P)H dehydrogenase, quinone 1 Cards Atlas NQO1ID375 GeneCards NQO1 Ensembl NQO1 CancerGene NQO1 Genatlas NQO1 GeneLynx NQO1 eGenome NQO1 euGene 1728 Genomic and cartography NQO1 - 16q22.1 chr16:68300810-68317893 - 16q22.1 (hg17- GoldenPath May_2004) Ensembl NQO1 - 16q22.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NQO1

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -440- Gene and transcription

Genbank AY281093 [ SRS ] AY281093 [ ENTREZ ]

Genbank M81600 [ SRS ] M81600 [ ENTREZ ]

Genbank BC000906 [ SRS ] BC000906 [ ENTREZ ]

Genbank BC007659 [ SRS ] BC007659 [ ENTREZ ]

Genbank J03934 [ SRS ] J03934 [ ENTREZ ]

RefSeq NM_000903 [ SRS ] NM_000903 [ ENTREZ ]

RefSeq NT_086851 [ SRS ] NT_086851 [ ENTREZ ] AceView NQO1 AceView - NCBI TRASER NQO1 Traser - Stanford

Unigene Hs.406515 [ SRS ] Hs.406515 [ NCBI ] HS406515 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P15559 [ SRS] P15559 [ EXPASY ] P15559 [ INTERPRO ]

Interpro IPR003680 NADHdh_2 [ SRS ] IPR003680 NADHdh_2 [ EBI ] CluSTr P15559

PF02525 Flavodoxin_2 [ SRS ] PF02525 Flavodoxin_2 [ Sanger Pfam ] pfam02525 [ NCBI-CDD ] Blocks P15559

PDB 1D4A [ SRS ] 1D4A [ PdbSum ], 1D4A [ IMB ]

PDB 1DXO [ SRS ] 1DXO [ PdbSum ], 1DXO [ IMB ]

PDB 1GG5 [ SRS ] 1GG5 [ PdbSum ], 1GG5 [ IMB ]

PDB 1H66 [ SRS ] 1H66 [ PdbSum ], 1H66 [ IMB ]

PDB 1H69 [ SRS ] 1H69 [ PdbSum ], 1H69 [ IMB ]

PDB 1KBO [ SRS ] 1KBO [ PdbSum ], 1KBO [ IMB ]

PDB 1KBQ [ SRS ] 1KBQ [ PdbSum ], 1KBQ [ IMB ]

PDB 1QBG [ SRS ] 1QBG [ PdbSum ], 1QBG [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 125860 [ map ] GENECLINICS 125860

SNP NQO1 [dbSNP-NCBI]

SNP NM_000903 [SNP-NCI]

SNP NQO1 [GeneSNPs - Utah] NQO1 [SNP - CSHL] NQO1] [HGBASE - SRS] General knowledge Family NQO1 [UCSC Family Browser] Browser SOURCE NM_000903 SMD Hs.406515 SAGE Hs.406515

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -441- Enzyme 1.6.99.2 [ Enzyme-SRS ] 1.6.99.2 [ Brenda-SRS ] 1.6.99.2 [ KEGG ] 1.6.99.2 [ WIT ] Amigo function|NAD(P)H dehydrogenase (quinone) activity Amigo function|cytochrome-b5 reductase activity Amigo component|cytoplasm Amigo process|electron transport Amigo process|nitric oxide biosynthesis Amigo function|oxidoreductase activity Amigo process|response to toxin Amigo process|synaptic transmission, cholinergic Amigo process|xenobiotic metabolism BIOCARTA Hypoxia and p53 in the Cardiovascular system KEGG Sterol Biosynthesis PubGene NQO1 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe NQO1 Related clones (RZPD - Berlin) PubMed PubMed 34 Pubmed reference(s) in LocusLink Bibliography DT-diaphorase. Ernster, L. Meth Enzymol 1967; 10: 309-317.

Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin. Jaiswal, AK. Biochemistry 1991; 30: 10647-10653.

Human dioxin inducible cytosolic NAD(P)H:menadione oxidoreductase. Jaiswal, AK, McBride OW, Adesnik M, and Nebert DW. Journal of Biological Chemistry 1988; 263, 13572-13578. Medline 1657151

DT-Diaphorase. Purification properties and function. Lind C, Cadenas E, Hochstein P, and Ernster L. Meth Enzymol 1990; 186, 287-301. Medline 2233301

NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: Characterization of a mutation which modulates DT-diaphorase activity

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -442- and mitomycin sensitivity. Traver RD, Horikoshi T, Danenberg KD, Stadlbauer THW, Danenberg PV, Ross D, and Gibson NW. Cancer Res 1992; 52, 797-802. Medline 1737339

DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Ross D, Siegel D, Beall H, Prakash AS, Mulcahy RT, and Gibson NW. Cancer Metastasis Rev 1993; 12, 83-101. Medline 8375023

Bioactivation of quinones by DT-Diaphorase. Molecular, biochemical and chemical studies. Ross D, Beall H, Traver RD, Siegel D, Phillips RM, and Gibson NW. Oncology Research 1994; 6, 493-500. Medline 7620217

Nicotinamide adenine dinucleotide (phosphate):quinone oxidoreductase (DT- diaphorase) as a target for bioreductive antitumor quinones: Quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. Beall HD, Murphy AM, Siegel D, Hargreaves RHJ, Butler J, and Ross D. Mol Pharmacol 1995; 48, 499-504. Medline 7565631

An alternatively spliced form of NQO1 (DT-diaphorase) messenger RNA lacking the putative quinone substrate binding site is present in human normal and tumor tissues. Gasdaska, PY, Fisher, H, and Powis G. Cancer Res 1995; 55, 2542-2547. Medline 7780966

The three dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy. Mechanism of the two electron reduction. Li R, Bianchet MA, Talalay P, and Amzel LM. Proc Natl Acad Sci USA 1995; 92, 8846-8850. Medline 7568029

NAD(P)H:quinone oxidoreductase expression and mitomycin C resistance developed by human colon cancer HCT 116 cells. Pan SS, Forrest GL, Akman SA, and Hu L-T. Cancer Res.1995; 55, 330-335. Medline 7812966

The NAD(P)H:quinoneoxidoreductase locus in human colon carcinoma HCT

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -443- 116 cells resistant to mitomycin C. Hu LT, Stamberb J, and Pan SS. Cancer Res 1996; 56, 5253-5259. Medline 8912865

The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Beyer RE, Segura-Aguilar J, Di Bernardo S, Cavazzoni M, Fato R, Fiorentini D, Galli M, Setti M, Landi L, and Lenaz G. Proc Natl Acad Sci USA 1996; 93, 2528-2532. Medline 8637908

Ethnic variation in the prevalence of a common NAD(P)H:quinone oxidoreductase polymorphism and its implications for anticancer chemotherapy. Kelsey KT, Wiencke JK, Christiani DC, Zuo Z, Spitz MR, Xu X, Lee BK, Schwartz BS, Traver RD, and Ross D. Brit J Cancer, 76, 852-854, 1997.

The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherol hydroquinone as a cellular antioxidant. Siegel D, Bolton EM, Burr JA, Liebler DC, and Ross D. Mol.Pharmacol 1997; 52, 300-305. Medline 9271353

Regulation and function of NAD(P)H:quinone oxidoreductase (NQO1). Kepa JK, Traver RD, Siegel D, Winski SL, and Ross D. Reviews in Toxicology 1997; 1, 53-73.

Characterization of a polymorphism in NAD(P)H: Quinone oxidoreductase (DT- diaphorase). Traver RD, Siegel D, Beall HD, Phillips RM, Gibson NW, Franklin WA, and Ross D. Brit J Cancer 1997; 75, 69-75. Medline 9000600

NAD(P)H:quinone oxidoreductase;polymorphisms and allele frequencies in Caucasian, Chinese and Canandian Native Indian and Inuit populations. Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, and Leeder JS. Pharmacogenetics 1998; 8, 305-313. Medline 9731717

Disruption of the DT-diaphorase (NQO1) gene in mice leads to increased menadione toxicity. Radjendirane V, Joseph P, Lee YH, Kimura S, Klein-Szanto AJP, Gonzalez FJ, and Jaiswal AK.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -444- J Biological Chemistry 1998; 273, 7382-7389. Medline 9516435

A new screening system for NAD(P)H:quinone oxidoreductase(NQO1)-directed antitumor quinones. Identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Winski S, Hargreaves RHJ, Butler J, and Ross D. Clinical Cancer Research 1998; 4, 3083-3088. Medline 9865924

Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:Quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Larson RA, Wang Y, Banerjee M, Wiemels J, Hartford C, Beau MM, and Smith MT. Blood 1999; 94, 803-807, 7-15. Medline 10397748

A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Moran JL, Siegel D, and Ross D. Proc Natl Acad Sci USA 1999; 96, 8150-8155. Medline 10393963

Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Siegel D, McGuinness SM, Winski S, and Ross D. Pharmacogenetics 1999; 9, 113-121. Medline 10208650

A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators . Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, and Greaves MF. Cancer Res 1999; 59, 4095-4099. Medline 10463613

Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: Species comparison and structural changes with substrate binding and release. Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, and Mario Amzel L. Proc Natl Acad Sci USA 2000; 97, 3177-3182. Medline 10706635

NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -445- Long DJ, Waikel RL, Wang XJ, Perlaky L, Roop DR, and Jaiswal AK. Cancer Res 2000; 60, 5913-5915. Medline 11085502

Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia. Naoe T, Takeyama K, Yokozawa T, Kiyoi H, Seto M, Uike N, Ino T, Utsunomiya A, Maruta A, Jin-nai I, Kamada N, Kubota Y, Nakamura H, Shimazaki C, Horiike S, Kodera Y, Saito H, Ueda R, Wiemels J, and Ohno R. Clinical Cancer Research 2000; 6, 4091-4095. Medline 11051261

NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, and Siegel D. Chemico-Biological Interactions 2000; 129, 77-97. Medline 11154736

Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues(1). Siegel D and Ross D. Free Radical Biology and Medicine 2000; 29, 246-253. Medline 11035253

Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1 Asher G, Lotem J, Cohen B, Sachs L, Shaul Y. Proc Natl Acad Sci USA 2001; 98: 1188-1193. Medline 11158615

NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin. Long DJ, Waikel RL, Wang XJ, Roop DR, Jaiswal AK. J Natl Cancer Inst 2001; 93: 1166-1170. Medline 11481389

NAD(P)H:quinone oxidoreductases. Ross D. Encyclopedia of Molecular Medicine 2001; 2208-2212.

Structure-based development of anticancer drugs. complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, and Amzel LM. Structure(Camb) 2001: 9, 659-667.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -446- Medline 11587640

Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, and Ross D. Mol Pharmacol.2001; 59, 263-268. Medline 11160862

Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Smith MT, Wang Y, Kane E, Rollinson S, Wiemels JL, Roman E, Roddam P, Cartwright R, and Morgan G. Blood 2001; 97, 1422-1426. Medline 11222389

NQO1 stabilizes p53 through a distinct pathway Asher G, Lotem J, Kama R, Sachs L, Shaul Y. Proc Natl Acad Sci USA 2002; 99: 3099-3104. Medline 11867746

Interaction of Human NAD(P)H:Quinone Oxidoreductase 1 (NQO1) with the Tumor Suppressor Protein p53 in Cells and Cell-free Systems Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA, Ross D. J Biol Chem 2003; 278: 10368-10373. Medline 12529318

NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics.AUTHORS Ross D, Siegel D. Methods in Enzymology 2004; 382: 115-144. Medline 15047100

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- David Ross 2001 Updated 06- David Ross 2004 Citation This paper should be referenced as such : Ross D . NQO1. Atlas Genet Cytogenet Oncol Haematol. December 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NQO1ID375.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -447- Ross D . NQO1. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NQO1ID375.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -448- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SERPINB5

Identity Note SERPINB5 is the most centromeric member of a cluster of 10 SERPIN genes which encode products with homology to known serine protease inhibitors. Other Maspin names Protease Inhibitor 5, PI5 Hugo SERPINB5 Location 18q21.33 BCL2 - FVT1- VPS4B - SERPINB5 - SERPINB12 - SERPINB13 DNA/RNA Description The SERPINB5 gene comprises seven exons and six introns which commonly encode a 2.6kb mRNA. Two alternatively processed splice variants have been reported but their significance is unknown. The ATG start is located in exon 2 with the stop codon in exon 7. Transcription Transcriptional control is complex. SERPINB5 may be induced by p53. In addition to a p53 consensus binding site, the promoter also contains functional Ets and AP-1 sites. In oestrogen receptor-positive breast cancer cells, expression may also be induced either directly or indirectly by the oestrogen antagonist, Tamoxifen. The cell-type specific expression of SERPINB5 is heavily influenced by the level of cytosine methylation in a region of sequence immediately upstream of exon 1. In normal cells that do not express SERPINB5, this region is: heavily methylated, associated with hypoacetylated histones and the local chromatin structure is inaccessible. The converse appears to be true for normal cells that express the gene. The analysis of the SERPINB5 promoter in a range of primary cell cultures provided the first formal demonstration that cytosine methylation is important in the regulation of normal cell-type specific gene expression. Pseudogene No known pseudogene. Protein

Description SERPINB5 encodes a 375 amino acid 42kDa protein, maspin, which shows sequence homology to serpins of the ovalbumin-type subfamily. In common with other family members, the protein is predicted to fold in such a way as to expose a short reactive site loop (amino acids 331- 345) on the surface. However, it is not currently clear whether maspin

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -449- actually acts as a true serine protease inhibitor and there are some suggestions that the RSL may represent primarily a serine protease substrate. Maspin is therefore generally classified as a non-inhibitory serpin. A number of isoforms of maspin have been detected in primary tissue samples and cultures. These may reflect processed or modified forms of the protein or else may represent degradation products. Expression Maspin is expressed strongly in specific populations of cells within a range of normal tissues: for example, in the myoepithelial cells of the breast or the basal epithelial cells of the bronchial airways. Other cell types within such tissues may generally show a complete lack of expression. Particular cell-type specific expression levels are likely to be controlled in the normal situation by strikingly different levels of cytosine promoter methylation. Many studies have reported differences in the expression and methylation status of SERPINB5 between tumours and matched normal tissue. However, given the complex pattern of cell-type specific expression/regulation of this gene and our general lack of knowledge of the identity and expression characteristics of the tumour progenitor cells, the pathological significance of these data are currently difficult to interpret. Localisation Sub-cellular localisation is variable depending on cell type. Consistent with predicted function, maspin may be found in certain cell types in cytoplasmic and peri-cellular locations. However, more recent studies have shown that maspin may be localised predominantly to the nucleus of certain normal or malignant cells. The role of the protein in the nucleus is not yet defined. Function The exact cellular role of maspin is not currently clear. Whilst the protein can specifically influence certain aspects of cell behaviour, often tumour and normal tissue derived expression data are at least superficially contradictory. This likely reflects our incomplete understanding of the function of the protein in different situations: that is, in the context of different cell types, differentiation states and gene expression backgrounds.

SERPINB5 was originally described as a breast tumour suppressor, a gene which was active in normal breast epithelial cells and which was down-regulated progressively towards malignancy with increasing degrees of tissue disorder being associated with less frequent instances of expression. Consistent with such a tumour suppressor function, work in vitro and in vivo suggested that maspin suppressed angiogenesis, reduced tumour invasiveness, growth, and metastasis and sensitised cells to apoptosis. It was suggested that maspin exerted these effects, at least in part, through modulation of plasminogen activation. In a breast cancer cell line, the maspin RSL was deemed to be critical for the inhibition of tumour cell invasion and the promotion of cell adhesion to extracellular matrix molecules.

However, recent studies have subsequently painted a more complex and perhaps contradictory picture. Maspin appears to have a critical role in early embryonic development. Homozygous loss of expression in

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -450- mice knockouts is lethal at the peri-implantation stage. The absence of the protein (-/-) disrupts the formation of the endodermal cell layer whilst maspin heterozygote knockout (+/-) endodermal cells grow more slowly than wild-type (+/+) cells. This is particularly interesting in the context of high-level maspin expression in tumours arising from organs of endodermal origin, such as the GI tract, lungs and thyroid. Furthermore, in LA7 cells, a well characterised rat adenocarcinoma in vitro model of mammary gland differentiation, maspin was shown to negatively regulate dome formation, possibly through the perturbation of cell adhesion. This observation suggests that at least in some situations, maspin expression can block differentiation processes. Homology Maspin is an ovalbumin (ov-) serpin, located in one of the two ov-serpin clusters (18q21.33, 6p25) in the human genome. Phylogenetic analysis has suggested that maspin is most closely related to the members of the 6q group and SERPINB8 on 18q. Mutations Epigenetics However, there are number of reports highlighting differences in promoter methylation status in primary human tumours compared to matched normal tissues. Whilst these studies are difficult to interpret given that cytosine methylation is used appropriately to control the cell- type expression of SERPINB5 in normal tissue (and therefore probably in the tumour cell progenitor), the striking observation of allele-specific differences in promoter methylation in pre-neoplastic gastric lesions suggests that pathological epigenetic alteration may be a significant factor in deregulating (or failing to appropriately inactivate) the gene in certain cancers. Somatic No somatic coding sequence mutations have been described for SERPINB5. Minimally, three validated non-synonymous and one synonymous cSNP are located within the gene at amino acids: 176 (C/T, Phe/Ser), 187 (C/G, Leu/Val), 298 (C/T, Ser/Ser) and 319 (A/G, Ile/Val).

The gene is not thought to be a frequent tumour amplification or translocation target. Implicated in Oncogenesis Maspin was classified as a breast cancer suppressor on the basis of functional and observational (immunohistochemical - IHC) studies. However, as more model systems, tumour types and corresponding normal tissues were analysed, the situation became more complex. Several microarray analyses of different human cancers indicated that maspin was frequently strongly expressed in tumour over normal tissue. Furthermore, strong and frequent expression was seen in some instances in pre-neoplastic lesions. Clearly, some tumours in a range of tissues express maspin and some do not, the subcellular localisation of the protein is variable, as is the methylation status of the promoter. Expression may correlate to some degree with the clinical behaviour or characteristics of particular tumours but in many cases the data from

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -451- different studies of the same diseases and tissues appear to be contradictory. One point that must be borne in mind is that a gene can be associated with good prognostic factors and improved survival and yet it can still be driving the malignant phenotype in the tumours in which it is expressed. In summary, many questions concerning the pathological role of maspin in human cancer remain unanswered.

Entity Breast cancer Note The terminal duct-lobular system of the breast comprises two specialised epithelial cell types, inner luminal secretory cells and outer contractile myoepithelial cells. It is thought that most breast tumours arise from cell types located within this structure. SERPINB5 is strongly expressed in the outer oestrogen receptor (ER) negative myoepithelial cells, where it is frequently located in both the nucleus and the cytoplasm. The luminal cells appear not to express maspin. The largest study (1068) of maspin expression in breast tumours scored a nuclear signal in 96% of carcinomas and a cytoplasmic signal in 35%. The nuclear staining was correlated with ER and progesterone receptor (PR) positivity whilst the cytoplasmic staining was associated with ER and PR negativity. It has been suggested that breast cancer initiates and is maintained from an aberrant adult stem cell. Maspin expression levels in tumours may therefore reflect a tendency for the tumour initiating stem cell component to differentiate towards cells which lack or retain maspin expression. These lesions may behave differently clinically in a way which is or is not directly related to maspin expression. This would not exclude the possibility that maspin is associated with some aspect of the multipotent stem cell phenotype nor that it might be involved in the actual differentiation process of particular cell types.

Entity Lung cancer Note Lung cancers generally arise from a component of the bronchial epithelium (BE). This pseudostratified lining of the airways comprises multipotent basal cells and specialised differentiated apical cells. The basal cells represent a reserve component of the epithelium which can differentiate into each of the mature cell types. Alveolar, stromal and normal differentiated epithelial cells are all typically negative for maspin expression. However, strong nuclear staining is seen in all airway basal cells (Figure: A, B). Maspin appears to be strongly expressed, generally in the cytoplasm and nucleus, in >95% of squamous cell carcinomas (Figure C) and 30-50% of adenocarcinomas. The expression of maspin is linked to the degree of promoter methylation and allele-specific transcript analysis suggests that in approximately 50% of lesions, expression in the tumour is predominantly driven from one chromosomal allele. Maspin is strongly and presumably inappropriately expressed in a significant fraction of pre-neoplastic bronchial lesions and a small fraction of histologically non-neoplastic epithelia (Figure D). The observation that maspin is strongly expressed

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -452- apparently appropriately in the normal stem cell-like basal component of the BE and that this expression appears to be down-regulated in the differentiated BE cells might suggest that the protein has a role in some aspect of maintenance of the basal cell (perhaps lung stem cell) phenotype and that a failure to inactivate maspin appropriately during differentiation may contribute to bronchial neoplasia.

The images show an immunohistochemical analysis of maspin expression in histologically normal lung (A, B, D) and NSCLC (C) tissues. The tumour cells (C) show intense nuclear and cytoplasmic staining. Panels A and B show typical staining patterns for normal bronchial tissue. Stromal cells are negative, basal epithelial cells in the airway epithelia in the normal sections show strong predominantly nuclear staining whilst apical epithelial cells are negative. A small number of hyperplastic epithelia show strong nuclear/cytoplasmic expression of maspin (D).

Entity Gastric cancer Note IHC reports are to some extent contradictory and this may reflect differing aetiologies. However, several studies suggest that maspin is strongly expressed in gastric carcinoma over normal mucosa. It has been reported that 80% of primary tumours and all gastric normal mucosa (GNM) with intestinal metaplasia (IM) show dense and diffuse cytoplasmic immunoreactivity while in contrast, GNM without IM show only weak or no staining. They further demonstrated that the GNM with IM show maspin promoter hypermethylation of one parental allele which would be consistent with expression occurring from a single allele in a clonal expansion, either as a result of an aberrant

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -453- demethylation event or else as a consequence of a failure to methylate appropriately one parental allele at some time during the differentiation process from a maspin expressing precursor. An alternative explanation, that SERPINB5 is developmentally imprinted in a GM with IM precursor, seems less likely but is nevertheless possible. Both alleles were hypermethylated in GNM without IM and both were generally hypomethylated in tumours.

Entity Pancreatic cancer Note Maspin is strongly expressed in most if not all pancreatic adenocarcinomas whereas normal pancreatic tissue appears to be negative or only weakly positive.

Entity Prostate cancer Note Whilst maspin expression in prostatic cancer was reportedly correlated with a less aggressive pathological and histological tumour grade, the protein was found to be expressed frequently in high grade prostate intraepithelial neoplasia, an observation which would be consistent with a role for maspin in pre-malignancy of the prostate.

Entity Melanoma Note Maspin appears to be expressed in a small fraction of primary melanomas but not normal melanocytes. This expression is correlated with the methylation status of the promoter.

Entity Thyroid Note Maspin expression has been reported in a large fraction of: papillary thyroid carcinomas, undifferentiated carcinomas and poorly differentiated carcinomas but only rarely in well differentiated tumours and not at all in normal thyroid, follicular adenomas or follicular carcinomas. The expression of maspin in thyroid carcinomas was therefore closely associated with a lack of differentiation of the tumour cells.

Entity Ovarian cancer Note Whilst normal ovarian surface epithelia have low levels of expression, maspin appears to be strongly expressed in a large fraction of primary tumours (37%). Tumours with high levels of maspin were more likely to be invasive and show cytoplasmic staining. Maspin over-expression was further associated with higher tumour grade, the presence of ascites and shorter survival. However, somewhat paradoxically, introduction of wild-type maspin into two ovarian cancer cell lines reduced their invasiveness.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -454- Entity Bladder cancer Note Maspin does not appear to be expressed in normal transitional cells of the bladder. However, a sizable fraction of tumours show strong nuclear and cytoplasmic expression; which is significantly correlated with muscle-invasive over non-invasive bladder cancer.

Breakpoints Note Maspin lies 158kb telomeric to BCL2, which is targeted in the t(14;18) translocation in follicular lymphoma. External links Nomenclature Hugo SERPINB5 GDB SERPINB5 SERPINB5 5268 serine (or cysteine) proteinase inhibitor, clade B Entrez_Gene (ovalbumin), member 5 Cards Atlas SerpinB5ID42267 GeneCards SERPINB5 Ensembl SERPINB5 CancerGene PI5 Genatlas SERPINB5 GeneLynx SERPINB5 eGenome SERPINB5 euGene 5268 Genomic and cartography SERPINB5 - 18q21.33 chr18:59295199-59323297 + 18q21.33 GoldenPath (hg17-May_2004) Ensembl SERPINB5 - 18q21.33 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SERPINB5 Gene and transcription

Genbank BC020713 [ SRS ] BC020713 [ ENTREZ ]

Genbank BX640597 [ SRS ] BX640597 [ ENTREZ ]

Genbank U04313 [ SRS ] U04313 [ ENTREZ ]

RefSeq NM_002639 [ SRS ] NM_002639 [ ENTREZ ]

RefSeq NT_086889 [ SRS ] NT_086889 [ ENTREZ ] AceView SERPINB5 AceView - NCBI TRASER SERPINB5 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -455- Unigene Hs.55279 [ SRS ] Hs.55279 [ NCBI ] HS55279 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P36952 [ SRS] P36952 [ EXPASY ] P36952 [ INTERPRO ]

Prosite PS00284 SERPIN [ SRS ] PS00284 SERPIN [ Expasy ]

Interpro IPR000215 Prot_inh_serpin [ SRS ] IPR000215 Prot_inh_serpin [ EBI ] Interpro IPR000240 SerpinB9_Maspin [ SRS ] IPR000240 SerpinB9_Maspin [ EBI ] CluSTr P36952 Pfam PF00079 Serpin [ SRS ] PF00079 Serpin [ Sanger ] pfam00079 [ NCBI-CDD ]

Smart SM00093 SERPIN [EMBL] Blocks P36952 Polymorphism : SNP, mutations, diseases OMIM 154790 [ map ] GENECLINICS 154790

SNP SERPINB5 [dbSNP-NCBI]

SNP NM_002639 [SNP-NCI]

SERPINB5 [GeneSNPs - Utah] SERPINB5 [SNP - CSHL] SERPINB5] [HGBASE - SNP SRS] General knowledge Family SERPINB5 [UCSC Family Browser] Browser SOURCE NM_002639 SMD Hs.55279 SAGE Hs.55279 Amigo process|cell motility Amigo component|nucleus Amigo function|serine-type endopeptidase inhibitor activity Amigo function|serine-type endopeptidase inhibitor activity Amigo process|transport PubGene SERPINB5 Other databases Probes Probe SERPINB5 Related clones (RZPD - Berlin) PubMed PubMed 35 Pubmed reference(s) in LocusLink Bibliography Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. Zhang M, Maass N, Magit D, Sager R.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -456- Cell Growth Differ 1997; 8: 179-186. Medline 9040939

Human ovalbumin serpin evolution: phylogenic analysis, gene organization, and identification of new PI8-related genes suggest that two interchromosomal and several intrachromosomal duplications generated the gene clusters at 18q21-q23 and 6p25. Scott FL, Eyre HJ, Lioumi M, Ragoussis J, Irving JA, Sutherland GA, Bird PI. Genomics 1999; 62: 490-499 Medline 10644448 p53 regulates the expression of the tumor suppressor gene maspin. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. J Biol Chem 2000; 275: 6051-6054 Medline 10692390

Expression of the tumor suppressor gene Maspin in human pancreatic cancers. Maass N, Hojo T, Ueding M, Luttges J, Kloppel G, Jonat W, Nagasaki K. Clin Cancer Res 2001; 7: 812-817 Medline 11309327

Proteomic dissection of dome formation in a mammary cell line: role of tropomyosin-5b and maspin. Zucchi I, Bini L, Valaperta R, Ginestra A, Albani D, Susani L, Sanchez JC, Liberatori S, Magi B, Raggiaschi R, Hochstrasser DF, Pallini V, Vezzoni P, Dulbecco R. Proc Natl Acad Sci USA 2001; 98: 5608-5613. Medline 11331746

Role for DNA methylation in the control of cell type specific maspin expression. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, Domann FE. Nat Genet 2002; 31: 175-179. Medline 12021783

Expression profiling of primary non-small cell lung cancer for target identification. Heighway J, Knapp T, Boyce L, Brennand S, Field JK, Betticher DC, Ratschiller D, Gugger M, Donovan M, Lasek A, Rickert P. Oncogene 2002; 21: 7749-7763. Medline 12400018

Maspin is up-regulated in premalignant prostate epithelia. Pierson CR, McGowen R, Grignon D, Sakr W, Dey J, Sheng S. Prostate 2002; 53: 255-262.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -457- Medline 12430137

Maspin is expressed in the nuclei of breast myoepithelial cells. Reis-Filho JS, Milanezi F, Schmitt FC. J Pathol 2002; 197: 272-273. Medline 12015753

The paradoxical expression of maspin in ovarian carcinoma. Sood AK, Fletcher MS, Gruman LM, Coffin JE, Jabbari S, Khalkhali-Ellis Z, Arbour N, Seftor EA, Hendrix MJ. Clin Cancer Res 2002; 8: 2924-2932. Medline 12231537

Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Akiyama Y, Maesawa C, Ogasawara S, Terashima M, Masuda T. Am J Pathol 2003; 163: 1911-1919. Medline 14578190

Maspin expression in invasive breast cancer: association with other prognostic factors. Mohsin SK, Zhang M, Clark GM, Craig Allred D. J Pathol 2003; 199: 432-435. Medline 12635133

Sufficiency of the reactive site loop of maspin for induction of cell-matrix adhesion and inhibition of cell invasion. Conversion of ovalbumin to a maspin- like molecule. Ngamkitidechakul C, Warejcka DJ, Burke JM, O'Brien WJ, Twining SS. J Biol Chem 2003; 278: 31796-31806. Epub 2003 Jun 10. Medline 12799381

Maspin - the most commonly-expressed gene of the 18q21.3 serpin cluster in lung cancer - is strongly expressed in preneoplastic bronchial lesions. Smith SL, Watson SG, Ratschiller D, Gugger M, Betticher DC, Heighway J. Oncogene 2003; 22: 8677-8687. Medline 14647462

Maspin plays an essential role in early embryonic development. Gao F, Shi HY, Daughty C, Cella N, Zhang M. Development 2004; 131: 1479-1489. Medline 14985257

Tamoxifen induces the expression of maspin through estrogen receptor-alpha. Liu Z, Shi HY, Nawaz Z, Zhang M.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -458- Cancer Lett. 2004; 209: 55-65. Medline 15145521

Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers. Ogasawara S, Maesawa C, Yamamoto M, Akiyama Y, Wada K, Fujisawa K, Higuchi T, Tomisawa Y, Sato N, Endo S, Saito K, Masuda T. Oncogene 2004; 23: 1117-1124. Medline 14743202

Expression and regulation of tumor suppressor gene maspin in human bladder cancer. Sugimoto S, Maass N, Takimoto Y, Sato K, Minei S, Zhang M, Hoshikawa Y, Junemann KP, Jonat W, Nagasaki K. Cancer Lett 2004; 203: 209-215. Medline 14732229

Aberrant expression of the maspin gene associated with epigenetic modification in melanoma cells. Wada K, Maesawa C, Akasaka T, Masuda T. J Invest Dermatol 2004; 122: 805-811. Medline 15086568

Maspin expression in normal lung and non-small-cell lung cancers: cellular property-associated expression under the control of promoter DNA methylation. Yatabe Y, Mitsudomi T, Takahashi T. Oncogene 2004; 23: 4041-4049. Medline 15048080

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Jim Heighway, Shirley Smith, Naomi Bowers, Daniel Betticher 2004 Citation This paper should be referenced as such : Heighway J, Smith S, Bowers N, Betticher D . SERPINB5. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SerpinB5ID42267.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -459- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TNF (tumor necrosis factor (TNF superfamily, member 2))

Identity Other TNFa (Tumor Necrosis Factor-a) names Cachectin TNF superfamily member 2 DIF Hugo TNF Location 6p21.3 DNA/RNA Description The human TNFa gene has 4 exons spanning 2,762bp on the region of chromosome 6p21.3. The expression of TNFa gene generates a TNFa mRNA with size of 1,669nt. The 3'-UTR region of TNFa mRNA contains a cluster of "AUUUA" elements that can be seen among many mRNAs with a short half-life, (AUUAUUUAUUAUUUAUUUAUUUAUUUAUUUAUUUA). A multiple NF-kB binding elements have been identified in the promoter region of TNFa gene. Protein

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -460-

The phylogenetic tree of TNF superfamily members.

Description The human TNFa protein contains 233 amino acids with a predicated molecular weight of 25.6 kDa. The TNFa is produced initially in a membrane-associated form, which is then subjected to enzymatic remove of the N-terminal 76 amino acids by TACE/ADAM17, a TNFa converting enzyme, to generate the soluble 17kDa TNFa molecule that forms homotrimer. TNFa is the first prototypic member identified in the TNF superfamily (TNFSF, Fig.1 and Table 1). The human TNF superfamily currently has 19 well-characterized members. Other members, such as TNFSF19, TNFSF21, and TNFSF22 have not been

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -461- well-established. Although each member has its own receptor preference, a functional overlapping, such as induction of apoptosis and NF-kB activation, has been observed among the majority of these members. In addition, as indicated in the phylogenetic tree in Figure 1, all of these members exhibit an evolutional conservation in their amino acid sequences, many of which show characteristics of type II membrane proteins. These features of TNF superfamily suggest that the members in this family may derived from the same ancestral gene. Several members contain a C-terminal conserved domain, named the TNF-homology domain that shares 20-30% of sequence identity. Except TNFSF1 (lymphotoxin a) and TNFSF3 (lymphotoxin b) that can form either homotrimer or heterotrimer, the active form of other members in this family is homotrimer. Expression TNFa is expressed virtually in every type of cells in response to inflammatory signals. Localisation membrane (type II membrane protein), extracellular soluble form, blood stream, and biological fluids. Function The most abundant cellular sources of TNFa are macrophage and monocyte. In response to inflammatory stimulation, macrophage or monocyte secretes TNFa that can induce apoptotic or necrotic cell death of certain tumor cell lines. In addition, TNFa is also capable of inducing cell proliferation and differentiation in many types of cells under certain circumstances. TNFa can be a pyrogen that causes fever by its direct action or by stimulation of interleukin 1 secretion. Sustained generation of TNFa in a variety of human diseases, especially cancer and severe infection, can cause cachexia-like syndrome. The increased expression of TNFa in adipose tissue was considered to be responsible for the development of obesity or diabetes due to the induction of insulin resistance by TNFa. All of above functional characteristics of TNFa are executed through specific members of the TNF receptor (TNFR) superfamily, mainly TNFR1, the primary receptor for soluble TNFa, and TNFR2, the predominant receptor for membrane-associated TNFa. These receptors trigger several intracellular signaling pathways, most importantly, the IkB kinase (IKK) and mitogen-activated protein kinase (MAPK) cascades, which govern gene expression through NF-kBNF-kB and AP-1 transcription factors, respectively. Implicated in Disease Arthritis, asthma, cancer, cardiovascular disorders, diabetes, HIV infection and AIDS, inflammatory bowel disease, lung fibrosis, obesity, septic shock, etc.. Cytogenetics Mutations or polymorphisms in the promoter or coding region of TNFa gene have been associated with asthma, celiac, septic shock susceptibility, silicosis, Psoriasis, GVHD, Leprosy, etc..

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -462- Hugo TNF GDB TNF Entrez_Gene TNF 7124 tumor necrosis factor (TNF superfamily, member 2) Cards Atlas TNFaID319 GeneCards TNF Ensembl TNF CancerGene TNF Genatlas TNF GeneLynx TNF eGenome TNF euGene 7124 Genomic and cartography TNF - 6p21.3 chr6:31651329-31654091 + 6p21.33 (hg17- GoldenPath May_2004) Ensembl TNF - 6p21.33 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TNF Gene and transcription

Genbank AB088112 [ SRS ] AB088112 [ ENTREZ ]

Genbank AF129756 [ SRS ] AF129756 [ ENTREZ ]

Genbank AJ249755 [ SRS ] AJ249755 [ ENTREZ ]

Genbank AJ270944 [ SRS ] AJ270944 [ ENTREZ ]

Genbank AL662801 [ SRS ] AL662801 [ ENTREZ ]

RefSeq NM_000594 [ SRS ] NM_000594 [ ENTREZ ]

RefSeq NT_086688 [ SRS ] NT_086688 [ ENTREZ ] AceView TNF AceView - NCBI TRASER TNF Traser - Stanford

Unigene Hs.241570 [ SRS ] Hs.241570 [ NCBI ] HS241570 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01375 [ SRS] P01375 [ EXPASY ] P01375 [ INTERPRO ]

Prosite PS00251 TNF_1 [ SRS ] PS00251 TNF_1 [ Expasy ]

Prosite PS50049 TNF_2 [ SRS ] PS50049 TNF_2 [ Expasy ]

Interpro IPR006053 TNF_abc [ SRS ] IPR006053 TNF_abc [ EBI ]

Interpro IPR006052 TNF_family [ SRS ] IPR006052 TNF_family [ EBI ]

Interpro IPR008983 TNF_like [ SRS ] IPR008983 TNF_like [ EBI ]

Interpro IPR003636 TNF_subf [ SRS ] IPR003636 TNF_subf [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -463- CluSTr P01375

Pfam PF00229 TNF [ SRS ] PF00229 TNF [ Sanger ] pfam00229 [ NCBI-CDD ]

Smart SM00207 TNF [EMBL]

Prodom PD002012 TNF_subf[INRA-Toulouse] Prodom P01375 TNFA_HUMAN [ Domain structure ] P01375 TNFA_HUMAN [ sequences sharing at least 1 domain ] Blocks P01375

PDB 1A8M [ SRS ] 1A8M [ PdbSum ], 1A8M [ IMB ]

PDB 1TNF [ SRS ] 1TNF [ PdbSum ], 1TNF [ IMB ]

PDB 2TUN [ SRS ] 2TUN [ PdbSum ], 2TUN [ IMB ]

PDB 4TSV [ SRS ] 4TSV [ PdbSum ], 4TSV [ IMB ]

PDB 5TSW [ SRS ] 5TSW [ PdbSum ], 5TSW [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 191160 [ map ] GENECLINICS 191160

SNP TNF [dbSNP-NCBI]

SNP NM_000594 [SNP-NCI]

SNP TNF [GeneSNPs - Utah] TNF [SNP - CSHL] TNF] [HGBASE - SRS] General knowledge Family TNF [UCSC Family Browser] Browser SOURCE NM_000594 SMD Hs.241570 SAGE Hs.241570 Amigo process|anti-apoptosis Amigo process|apoptosis Amigo process|cell-cell signaling Amigo process|inflammatory response Amigo component|integral to membrane Amigo process|leukocyte cell adhesion Amigo process|necrosis Amigo process|regulation of transcription, DNA-dependent Amigo process|response to virus Amigo process|signal transduction Amigo component|soluble fraction Amigo function|tumor necrosis factor receptor binding BIOCARTA HIV-I Nef: negative effector of Fas and TNF BIOCARTA Cells and Molecules involved in local acute inflammatory response BIOCARTA Acetylation and Deacetylation of RelA in The Nucleus

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -464- BIOCARTA Cadmium induces DNA synthesis and proliferation in macrophages BIOCARTA Cytokine Network BIOCARTA Free Radical Induced Apoptosis BIOCARTA Adhesion and Diapedesis of Granulocytes BIOCARTA Stress Induction of HSP Regulation BIOCARTA IL-10 Anti-inflammatory Signaling Pathway BIOCARTA Signal transduction through IL1R BIOCARTA Cytokines and Inflammatory Response BIOCARTA Keratinocyte Differentiation BIOCARTA Msp/Ron Receptor Signaling Pathway BIOCARTA NF-kB Signaling Pathway BIOCARTA NFkB activation by Nontypeable Hemophilus influenzae BIOCARTA Regulation of transcriptional activity by PML Mechanism of Gene Regulation by Peroxisome Proliferators via BIOCARTA PPARa(alpha) BIOCARTA SODD/TNFR1 Signaling Pathway BIOCARTA TNF/Stress Related Signaling BIOCARTA Chaperones modulate interferon Signaling Pathway BIOCARTA TNFR1 Signaling Pathway BIOCARTA Visceral Fat Deposits and the Metabolic Syndrome PubGene TNF Other databases Probes Probe TNF Related clones (RZPD - Berlin) PubMed PubMed 498 Pubmed reference(s) in LocusLink Bibliography The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC. Curr Drug Targets Inflamm Allergy 2002; 1(4): 327-341. Medline 14561180

The IL-1 family and inflammatory diseases. Dinarello CA. Clin Exp Rheumatol 2002; 20(5 Suppl 27): S1-13. Medline 14989423

Signalling pathways of the TNF superfamily: a double-edged sword. Aggarwal BB.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -465- Nat Rev Immunol 2003; 3(9): 745-756. Medline 12949498

A co-evolution perspective of the TNFSF and TNFRSF families in the immune system. Collette Y, Gilles A, Pontarotti P, Olive D. Trends Immunol 2003; 24(7): 387-394. Medline 12860530

The signaling adaptors and pathways activated by TNF superfamily. Dempsey PW, Doyle SE, He JQ, Cheng G Cytokine Growth Factor Rev 2003; 14(3-4): 193-209. Medline 12787559

Adding facets to TNF signaling. The JNK angle. Lin ZG. Mol Cell 2003; 12(4): 795-796. Medline 14580328

Anti-TNF-alpha therapies: the next generation. Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL. Nat Rev Drug Discov 2003; 2(9): 736-746. Medline 12951580

Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Szlosarek PW, Balkwill FR. Lancet Oncol 2003; 4(9): 565-573. Medline 12965278

The TNF superfamily. Ware CF. Cytokine Growth Factor Rev 2003; 14(3-4): 181-184. Medline 12787557

Inflammation: the link between insulin resistance, obesity and diabetes. Dandona P, Aljada A, Bandyopadhyay A. Trends Immunol 2004; 25(1): 4-7. Medline 14698276

Tumor necrosis factor: an apoptosis JuNKie? Varfolomeev EE, Ashkenazi A. Cell 2004; 116(4): 491-497. Medline 14980217

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -466- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Fei Chen 2004 Citation This paper should be referenced as such : Chen F . TNF (tumor necrosis factor (TNF superfamily, member 2)). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TNFaID319.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -467- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRC8 (translocation in renal carcinoma, chromosome 8 gene)

Identity Other RNF139 names RCA1 HRCA1 MGC31961 8_125443572 Location 8q24.31 DNA/RNA Description The TRC8 gene covers 13.96 kb. The gene contains 2 confirmed introns, 2 of which are alternative. The gene showed similarity to the hereditary basal cell carcinoma/segment polarity gene, 'patched' (PTCH) This similarity involved 2 regions of 'patched,' the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog (SHH). In the t(3;8) translocation, TRC8 was found to be fused to FHIT and disrupted within the sterol-sensing domain. In contrast, the FHIT coding region was maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched, TRC8 might function as a signaling receptor, and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid. Protein

Description 664 amino acids Localisation Plasma membrane Function The protein encoded by this gene is a multi-membrane spanning protein containing a RING-H2 finger. This protein is located in the endoplasmic reticulum, and has been shown to possess ubiquitin ligase activity. This gene was found to be interrupted by a t(3:8) translocation in a family with hereditary renal and non-medulary thyroid cancer. Studies of the Drosophila counterpart suggested that this protein may interact with tumor suppressor protein VHL, as well as with COPS5/JAB1, a protein responsible for the degradation of tumor suppressor CDKN1B/P27KIP Implicated in

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -468- Entity t(3;8)(p14.2;q24.1) and hereditary renal cell cancer. Disease familial renal cell cancer Cytogenetics Disruption of the gene because of the t(3;8) translocation. Hybrid/Mutated FHIT/TRC8. Although studies demonstrated that the 3p14.2 Gene breakpoint interrupted the fragile histidine triad gene (FHIT) in its 5- prime noncoding region, several reasons made it unlikely that FHIT is causally related to renal or other malignancies.

External links Nomenclature GDB RNF139 Entrez_Gene RNF139 11236 ring finger protein 139 Cards Atlas TRC8ID500 GeneCards RNF139 Ensembl RNF139 CancerGene RCA1 Genatlas RNF139 GeneLynx RNF139 eGenome RNF139 euGene 11236 Genomic and cartography RNF139 - 8q24.31 chr8:125556189-125570040 + 8q24.13 GoldenPath (hg17-May_2004) Ensembl RNF139 - 8q24.13 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RNF139 Gene and transcription

Genbank AF064800 [ SRS ] AF064800 [ ENTREZ ]

Genbank AA455970 [ SRS ] AA455970 [ ENTREZ ]

Genbank AF064801 [ SRS ] AF064801 [ ENTREZ ]

Genbank AK001602 [ SRS ] AK001602 [ ENTREZ ]

Genbank AK025043 [ SRS ] AK025043 [ ENTREZ ]

RefSeq NM_007218 [ SRS ] NM_007218 [ ENTREZ ]

RefSeq NT_086743 [ SRS ] NT_086743 [ ENTREZ ] AceView RNF139 AceView - NCBI TRASER RNF139 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -469- Unigene Hs.492751 [ SRS ] Hs.492751 [ NCBI ] HS492751 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O75485 [ SRS] O75485 [ EXPASY ] O75485 [ INTERPRO ]

Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ]

Interpro IPR001841 Znf_ring [ SRS ] IPR001841 Znf_ring [ EBI ] CluSTr O75485 Pfam PF00097 zf-C3HC4 [ SRS ] PF00097 zf-C3HC4 [ Sanger ] pfam00097 [ NCBI-CDD ]

Smart SM00184 RING [EMBL] Blocks O75485 Polymorphism : SNP, mutations, diseases OMIM 603046 [ map ] GENECLINICS 603046

SNP RNF139 [dbSNP-NCBI]

SNP NM_007218 [SNP-NCI]

SNP RNF139 [GeneSNPs - Utah] RNF139 [SNP - CSHL] RNF139] [HGBASE - SRS] General knowledge Family RNF139 [UCSC Family Browser] Browser SOURCE NM_007218 SMD Hs.492751 SAGE Hs.492751 Amigo component|integral to plasma membrane Amigo process|protein ubiquitination Amigo function|receptor activity Amigo process|signal transduction Amigo component|ubiquitin ligase complex Amigo function|ubiquitin-protein ligase activity Amigo function|zinc ion binding PubGene RNF139 Other databases Probes PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography Hereditary renal-cell carcinoma associated with a chromosomal translocation. Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC, Brown RS. N Engl J Med 1979; 301(11): 592-595. Medline 470981

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -470-

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Gemmill RM, Bemis LT, Lee JP, Sozen MA, Baron A, Zeng C, Erickson PF, Hooper JE, Drabkin HA. Oncogene 2002; 21(22): 3507-3516. Medline 12032852

Sonic Hedgehog signalling in the developing and adult brain. Charytoniuk D, Porcel B, Rodriguez Gomez J, Faure H, Ruat M, Traiffort E. J Physiol Paris 2002; 96(1-2): 9-16. Medline 11755778

RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM. Proc Natl Acad Sci USA 1999; 96(20): 11364-11369. Medline 10500182

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched- related gene, TRC8. Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA. Proc Natl Acad Sci USA 1998; 95(16): 9572-9577. Medline 9689122

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Anita Bonné, Eric Schoenmakers, Ad Geurts van Kessel. 2004 Citation This paper should be referenced as such : Bonné A, Schoenmakers E, Geurts van Kessel A. . TRC8 (translocation in renal carcinoma, chromosome 8 gene). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TRC8ID500.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -471- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCL11B (B-cell lymphoma/leukaemia 11B)

Identity Note BCL11B (14q32.2): FISH with RP11 BAC clones 1127d7 (green label) and 1057p17 (red label) showing split signal as indicated above right (dotted lines). Observe telomeric part of chr 14 translocated to the der(5) as revealed by the red doublet signal. The der(14) partner in turn receives a microinsertion containing material from chr 5. Analysis was performed on the pediatric T-ALL cell line CCRF-CEM which carries t(5;14)(q35.1;q32) resulting in ectopic expression of of NKX2-5 (2Mbp telomeric of, and closely related to, the standard partner gene TLX3 at 5q35) by juxtaposition with the far downstream region of BCL11B. Other CTIP2 (Ctip-2) chicken ovalbumin upstream promoter transcription names factor (COUP-TF)-interacting protein Rit1 zinc finger protein hRit1 alpha (not to be confused with RIT1

on chr. 1q22) Hugo BCL11B Location 14q32.2

DNA/RNA

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Description ORF comprises 4 exons, exon 3 being alternately spliced, while the 3' part of exon 4 is untranslated. Alternative splice variants due to presence (var.1) or absence (var.2) of exon 3. Transcription In a telomeric --> centromeric orientation. Protein

Description 894 amino acids, 95.5 kDa; contains 6 krueppel-like Zn-finger domains and a proline-rich region Expression Normal expression in thymus and brain; malignant expression in T-cell neoplasia and Ewing-family tumors. Localisation Inner nuclear membrane; colocalization with heterochromatin protein (HP1) and histone deacetylase SIRT1 suggests role as transcriptional repressor. Function Poorly defined; transcriptional repressor; developmentally regulates thymic differentiation and survival; inhibits HIV-1 Tat transactivation and repression of viral replication. Homology BCL11A on chromosome 2p13. Mutations Somatic Unrecorded in humans. Biallelic mutation/deletion in mouse thymic lymphomas induced by ionizing radiation. Implicated in Entity T-cell acute lymphoblastic leukemia (T-ALL) with t(5;14)(q35;q32) --> TLX3 - BCL11B Disease First detected as translocation partner of TLX3 (alias HOX11L2) in 15- 20% pediatric cortical T-ALL with possible male bias; subsequently confirmed in adult T-ALL, albeit less frequently. Prognosis May be poor via strong cytogenetic assocation with TLX3 which reportedly confers adverse prognosis. Cytogenetics Additional known recurrent rearrangements reportedly absent from t(5;14) patients. Oncogenesis Distal regulatory elements drive ectopic expression of TLX3 in T-ALL

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -473- and possibly other related NK-family Hox genes, viz. NKX2-5. Tumor suppressor role reported in mouse yet to be confirmed in man.

Breakpoints

Note t(5;14) breakpoints are widely scattered over 1.2 Mbp downstream of BCL11B probably targeting distal enhancer(s) posited to lie in the "gene desert" separating BCL11b from VRK1. This region has been recently shown to carry multiple Dnase-I sensitive sites in T-cells which may represent a locus control region. The solitary AML breakpoint lies upstream of BCL11B and its significance has yet to be established. External links Nomenclature Hugo BCL11B GDB BCL11B Entrez_Gene BCL11B 64919 B-cell CLL/lymphoma 11B (zinc finger protein) Cards Atlas BCL11BID392 GeneCards BCL11B

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -474- Ensembl BCL11B CancerGene BCL11B Genatlas BCL11B GeneLynx BCL11B eGenome BCL11B euGene 64919 Genomic and cartography BCL11B - 14q32.2 chr14:98705377-98807575 - 14q32.2 (hg17- GoldenPath May_2004) Ensembl BCL11B - 14q32.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BCL11B Gene and transcription

Genbank AB043584 [ SRS ] AB043584 [ ENTREZ ]

Genbank AF086271 [ SRS ] AF086271 [ ENTREZ ]

Genbank AJ404614 [ SRS ] AJ404614 [ ENTREZ ]

RefSeq NM_022898 [ SRS ] NM_022898 [ ENTREZ ]

RefSeq NM_138576 [ SRS ] NM_138576 [ ENTREZ ]

RefSeq NT_086807 [ SRS ] NT_086807 [ ENTREZ ] AceView BCL11B AceView - NCBI TRASER BCL11B Traser - Stanford

Unigene Hs.510396 [ SRS ] Hs.510396 [ NCBI ] HS510396 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9C0K0 [ SRS] Q9C0K0 [ EXPASY ] Q9C0K0 [ INTERPRO ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr Q9C0K0 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00355 ZnF_C2H2 [EMBL]

Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom Q9C0K0 BC1B_HUMAN [ Domain structure ] Q9C0K0 BC1B_HUMAN [ sequences sharing at least 1 domain ] Blocks Q9C0K0 Polymorphism : SNP, mutations, diseases OMIM 606558 [ map ]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -475- GENECLINICS 606558

SNP BCL11B [dbSNP-NCBI]

SNP NM_022898 [SNP-NCI]

SNP NM_138576 [SNP-NCI]

SNP BCL11B [GeneSNPs - Utah] BCL11B [SNP - CSHL] BCL11B] [HGBASE - SRS] General knowledge Family BCL11B [UCSC Family Browser] Browser SOURCE NM_022898 SOURCE NM_138576 SMD Hs.510396 SAGE Hs.510396 Amigo function|nucleic acid binding Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|zinc ion binding PubGene BCL11B Other databases Probes Probe BCL11B Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffe M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R. Leukemia 2001; 15(10): 1495-1504. Medline 11587205

The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ. Blood 2001; 98(12): 3413-3420. Medline 11719382

COUP-TF (chicken ovalbumin upstream promoter transcription factor)- interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -476- Avram D, Fields A, Senawong T, Topark-Ngarm A, Leid M. Biochem J 2002; 368(Pt 2): 555-563. Medline 12196208

Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG. Genes Chromosomes Cancer 2003; 37(1): 84-91. Medline 12661009

The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Nagel S, Kaufmann M, Drexler HG, MacLeod RA. Cancer Res 2003; 63(17): 5329-5334. Medline 14500364

Recruitment of Tat to heterochromatin protein HP1 via interaction with CTIP2 inhibits human immunodeficiency virus type 1 replication in microglial cells. Rohr O, Lecestre D, Chasserot-Golaz S, Marban C, Avram D, Aunis D, Leid M, Schaeffer E. J Virol 2003; 77(9): 5415-5427. Medline 12692243

Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression. Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S, Leid M J Biol Chem 2003; 278(44): 43041-43050. Medline 12930829

Homozygous deletions and point mutations of the Rit1/Bcl11b gene in gamma- ray induced mouse thymic lymphomas. Wakabayashi Y, Inoue J, Takahashi Y, Matsuki A, Kosugi-Okano H, Shinbo T, Mishima Y, Niwa O, Kominami R. Biochem Biophys Res Commun 2003; 301(2): 598-603. Medline 12565905

Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y, Hitomi J, Yamamoto T, Utsuyama M, Niwa O, Aizawa S, Kominami R. Nat Immunol 2003; 4(6): 533-539. Medline 12717433

A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene. Bezrookove V, van Zelderen-Bhola SL, Brink A, Szuhai K, Raap AK, Barge R,

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -477- Beverstock GC, Rosenberg C. Cancer Genet Cytogenet 2004; 149(1): 72-76. Medline 15104287

Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Mechinaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Vande Velde I, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N; EORTC-CLG, Blood 2004; 103(2): 442-450 Medline 14504110

Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. Crawford GE, Holt IE, Mullikin JC, Tai D, Blakesley R, Bouffard G, Young A, Masiello C, Green ED, Wolfsberg TG, Collins FS; National Institutes Of Health Intramural Sequencing Center. Proc Natl Acad Sci U S A 2004; 101(4): 992-997. Medline 14732688

BCL11B Rearrangements probably target T-Cell neoplasia rather than AML. MacLeod RAF, Nagel S, Drexler HG. Cancer Genet Cytogenet 2004, in press.

Involvement of V(D)J recombinase in the generation of intragenic deletions in the Rit1/Bcl11b tumor suppressor gene in gamma-ray-induced thymic lymphomas and in normal thymus of the mouse. Sakata J, Inoue J, Ohi H, Kosugi-Okano H, Mishima Y, Hatakeyama K, Niwa O, Kominami R. Carcinogenesis 2004 Jun; 25(6): 1069-1075. Medline 14754877

Two distinct methods analyzing chromatin structure using centrifugation and antibodies to modified histone H3: both provide similar chromatin states of the Rit1/Bcl11b gene. Togashi T, Obata M, Aoyagi Y, Kominami R, Mishima Y. Biochem Biophys Res Commun 2004; 313(3): 489-495. Medline 14697215

Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia. Van Zutven LJ, Velthuizen SC, Wolvers-Tettero IL, Van Dongen JJ, Poulsen TS, MacLeod RA, Beverloo HB, Langerak AW. Haematologica. 2004 Jun; 89(6): 671-678.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -478- Medline 15194534

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Roderick A F MacLeod, Stefan Nagel 2004 Citation This paper should be referenced as such : MacLeod RAF, Nagel S . BCL11B (B-cell lymphoma/leukaemia 11B). Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BCL11BID392.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -479- Atlas of Genetics and Cytogenetics in Oncology and Haematology

DDIT3 (DNA damage inducible transcript 3)

Identity Other CHOP (C/EBP homologous protein) names CHOP-10 (C/EBP homologous protein 10) GADD153 (Growth arrest and DNA damage inducible gene 153) C/EBP zeta (CCAAT/enhancer binding protein zeta) Hugo DDIT3 Location 12q13.1-q13.2 DNA/RNA Description The gene has 4 exons (94 bp, 48 bp, 167 bp and 586 bp). The start codon is in the exon 3. The total genomic sequence spanning the DDIT3 gene is approx. 3 Kb. Transcription Transcript lenght: 1,1 Kb. Protein

Description 169 amino acids, 29 Kda. DDIT3 contains a carboxy-terminal region (bZIP) formed by a DNA-binding basic domain and a leucine zipper dimerization domain. Expression DDIT3 is expressed ubiquitously. It is usually expressed at undetectable levels and its expression is induced by cellular stress. Localisation Nuclear. Function DDIT3 does not form homodimers and it functions as a dominant negative C/EBP forming heterodimers with other C/EBP members and preventing their binding to C/EBP sequences in the DNA. DDIT3 is

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -480- implicated in adipogenesis, erythropoiesis, in the induction of growth arrest and in the endoplasmic reticulum stress response. Homology DDIT3 belongs to the CCAAT/enhancer binding protein (C/EBP) family of transcription factors and it has been found to have high homology in hamster, rat and mouse. Mutations Germinal In the mouse, germine mutation in the ddit3 gene produces a decrease in the programmed cell death induced by perturbation in the endoplasmic reticulum function. On the other hand, while DDIT3 inhibits adipogenesis in 3T3-L1 preadipocytes, transgenic mice expressing DDIT3 from a housekeeping promoter display normal adipogenesis. Implicated in Note The DDIT3 gene is implicated in two chromosomal translocations associated to the myxoid liposarcoma (MLS). These fusion proteins generated as a result of chromosomal rearragements are used to monitor diagnosis and treatment.

Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3. Disease Myxoid liposarcoma (MLS). Hybrid/Mutated 9 different types of fusions between the genes FUS and DDIT3 have Gene been reported. The most frequent rearragements join the exons 5, 7 or 8 of FUS with the exon 2 of DDIT3. Oncogenesis The unequivocally relation between FUS/DDIT3 and the MLS was shown by the generation of a transgenic mouse model expressing FUS/DDIT3 from a housekeeping promoter.

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Entity t(12;22)(q13;q12) chromosomal translocation. It produces the fusion protein EWS/DDIT3. Disease Myxoid liposarcoma (MLS). Hybrid/Mutated 2 different types of fusions between the genes EWS and DDIT3 have Gene been reported. The first one joins the exon 7 of EWS with the exon 2 of DDIT3, while the second one joins the exon 10 of EWS with the exon 2 of DDIT3.

Breakpoints

External links Nomenclature Hugo DDIT3 GDB DDIT3 Entrez_Gene DDIT3 1649 DNA-damage-inducible transcript 3 Cards Atlas DDIT3ID80 GeneCards DDIT3 Ensembl DDIT3 CancerGene DDIT3 Genatlas DDIT3 GeneLynx DDIT3 eGenome DDIT3 euGene 1649 Genomic and cartography DDIT3 - chr12:56196640-56200567 - 12q13.3 (hg17- GoldenPath May_2004) Ensembl DDIT3 - 12q13.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -482- OMIM Disease map [OMIM] HomoloGene DDIT3 Gene and transcription

Genbank AY880949 [ SRS ] AY880949 [ ENTREZ ]

Genbank AA476561 [ SRS ] AA476561 [ ENTREZ ]

Genbank AI658803 [ SRS ] AI658803 [ ENTREZ ]

Genbank AV729744 [ SRS ] AV729744 [ ENTREZ ]

Genbank BC003637 [ SRS ] BC003637 [ ENTREZ ]

RefSeq NM_004083 [ SRS ] NM_004083 [ ENTREZ ]

RefSeq NT_086796 [ SRS ] NT_086796 [ ENTREZ ] AceView DDIT3 AceView - NCBI TRASER DDIT3 Traser - Stanford

Unigene Hs.505777 [ SRS ] Hs.505777 [ NCBI ] HS505777 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35638 [ SRS] P35638 [ EXPASY ] P35638 [ INTERPRO ]

Prosite PS50217 BZIP [ SRS ] PS50217 BZIP [ Expasy ]

Prosite PS00036 BZIP_BASIC [ SRS ] PS00036 BZIP_BASIC [ Expasy ]

Interpro IPR004827 TF_bZIP [ SRS ] IPR004827 TF_bZIP [ EBI ] CluSTr P35638

Smart SM00338 BRLZ [EMBL] Blocks P35638 Polymorphism : SNP, mutations, diseases OMIM 126337 [ map ] GENECLINICS 126337

SNP DDIT3 [dbSNP-NCBI]

SNP NM_004083 [SNP-NCI]

SNP DDIT3 [GeneSNPs - Utah] DDIT3 [SNP - CSHL] DDIT3] [HGBASE - SRS] General knowledge Family DDIT3 [UCSC Family Browser] Browser SOURCE NM_004083 SMD Hs.505777 SAGE Hs.505777 Amigo process|cell cycle arrest Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|response to DNA damage stimulus Amigo function|transcription corepressor activity

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -483- Amigo function|transcription factor activity BIOCARTA p38 MAPK Signaling Pathway PubGene DDIT3 Other databases Probes Probe DDIT3 Related clones (RZPD - Berlin) PubMed PubMed 28 Pubmed reference(s) in LocusLink Bibliography

Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willen H, Rydholm A, Mitelman F. Genes Chromosomes Cancer 1992 Nov; 5(4): 278-285. Medline 1283316

CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Barone MV, Crozat A, Tabaee A, Philipson L, Ron D. Genes Dev 1994 Feb 15; 8(4): 453-464. Medline 8125258

Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). Batchvarova N, Wang XZ, Ron D. EMBO J 1995 Oct 2; 14(19): 4654-4661. Medline 7588595

Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Cao Z, Umek RM, McKnight SL. Genes Dev 1991 Sep; 5(9): 1538-1552. Medline 1840554

Regulation of the C/EBP-related gene gadd153 by glucose deprivation. Carlson SG, Fawcett TW, Bartlett JD, Bernier M, Holbrook NJ. Mol Cell Biol 1993 Aug; 13(8): 4736-4744. Medline 8336711

Regulated expression and functional role of the transcription factor CHOP (GADD153) in erythroid growth and differentiation. Coutts M, Cui K, Davis KL, Keutzer JC, Sytkowski AJ. Blood 1999 May 15; 93(10): 3369-3378. Medline 10233889

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -484-

Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Crozat A, Aman P, Mandahl N, Ron D. Nature 1993 Jun 17; 363(6430): 640-644. Medline 8510758

Novel interaction between the transcription factor CHOP (GADD153) and the ribosomal protein FTE/S3a modulates erythropoiesis. Cui K, Coutts M, Stahl J, Sytkowski AJ. J Biol Chem 2000 Mar 17; 275(11): 7591-7596. Medline 10713066

The role of C/EBP genes in adipocyte differentiation. Darlington GJ, Ross SE, MacDougald OA. J Biol Chem 1998 Nov 13; 273(46): 30057-30060. Medline 9804754

Mammalian genes coordinately regulated by growth arrest signals and DNA- damaging agents. Fornace AJ Jr, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J, Holbrook NJ. Mol Cell Biol 1989 Oct; 9(10): 4196-4203. Medline 2573827

A novel type of EWS-CHOP fusion gene in two cases of myxoid liposarcoma. Hosaka T, Nakashima Y, Kusuzaki K, Murata H, Nakayama T, Nakamata T, Aoyama T, Okamoto T, Nishijo K, Araki N, Tsuboyama T, Nakamura T, Toguchida J. J Mol Diagn 2002 Aug; 4(3): 164-171. Medline 12169678

Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis. Knight JC, Renwick PJ, Cin PD, Van den Berghe H, Fletcher CD. Cancer Res 1995 Jan 1; 55(1): 24-27. Medline 7805034

Biological role of the CCAAT/enhancer-binding protein family of transcription factors. Lekstrom-Himes J, Xanthopoulos KG. J Biol Chem 1998 Oct 30; 273(44): 28545-28548. Medline 9786841

Fusion of the EWS and CHOP genes in myxoid liposarcoma. Panagopoulos I, Hoglund M, Mertens F, Mandahl N, Mitelman F, Aman P. Oncogene 1996 Feb 1; 12(3): 489-494. Medline 8637704

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Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia. Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N, Aman P. Oncogene 1997 Sep; 15(11): 1357-1362. Medline 9315104

A novel FUS/CHOP chimera in myxoid liposarcoma. Panagopoulos I, Mertens F, Isaksson M, Mandahl N. Biochem Biophys Res Commun 2000 Dec 29; 279(3): 838-845. Medline 11162437

Isolation, characterization and chromosomal localization of the human GADD153 gene. Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace AJ Jr, McBride OW, Holbrook NJ. Gene 1992 Jul 15; 116(2): 259-267. Medline 1339368

The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Perez-Losada J, Pintado B, Gutierrez-Adan A, Flores T, Banares-Gonzalez B, del Campo JC, Martin-Martin JF, Battaner E, Sanchez-Garcia I. Oncogene 2000 May 11; 19(20): 2413-2422. Medline 10828883

Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma. Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia MA, Perez-Mancera PA, Pintado B, Flores T, Battaner E, Sanchez-Garcia I. Oncogene 2000 Dec 7; 19(52): 6015-6022. Medline 11146553

Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice. Perez-Mancera PA, Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia MA, Flores T, Battaner E, Gutierrez-Adan A, Pintado B, Sanchez-Garcia I. Oncogene 2002 Mar 7; 21(11): 1679-1684. Medline 11896599

Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose- regulated proteins. Price BD, Calderwood SK. Cancer Res 1992 Jul 1; 52(13): 3814-3817.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -486- Medline 1617653

Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Rabbitts TH, Forster A, Larson R, Nathan P. Nat Genet 1993 Jun; 4(2): 175-180. Medline 7503811

CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Ron D, Habener JF. Genes Dev 1992 Mar; 6(3): 439-453. Medline 1547942

Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Ubeda M, Wang XZ, Zinszner H, Wu I, Habener JF, Ron D. Mol Cell Biol 1996 Apr; 16(4): 1479-1489. Medline 8657121

Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, Mi LJ, Boorstein R, Kreibich G, Hendershot LM, Ron D. Mol Cell Biol 1996 Aug; 16(8): 4273-4280. Medline 8754828

Identification of novel stress-induced genes downstream of chop. Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D. EMBO J 1998 Jul 1; 17(13): 3619-3630. Medline 9649432

Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Yeh WC, Cao Z, Classon M, McKnight SL. Genes Dev 1995 Jan 15; 9(2): 168-181. Medline 7531665

CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D. Genes Dev 1998 Apr 1; 12(7): 982-995. Medline 9531536

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -487- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Pedro A Pérez-Mancera, Isidro Sanchez-Garcia 2004 Citation This paper should be referenced as such : Pérez-Mancera PA, Sanchez-Garcia I . DDIT3 (DNA damage inducible transcript 3). Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/DDIT3ID80.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -488- Atlas of Genetics and Cytogenetics in Oncology and Haematology

FUS (fusion involved in t(12;16) in malignant liposarcoma)

Identity Other TLS (translocated in liposarcoma) names Hugo FUS Location 16p11.2 DNA/RNA Description The gene has 15 exons, and the total genomic sequence spanning the FUS gene is approx. 12 Kb. Transcription Transcript lenght: 1,9 Kb. There are two isoforms produced by an alternative splicing that involved the exon 4a (145 bp) or the exon 4b (142 bp). Protein

Description 526 amino acids (isoform with the exon 4a) or 525 aa (isoform with the exon 4b), 68 Kda. The protein contains different domains: a N-terminal SYQG-rich region; a RGG-rich region; a RNA binding domain; a RGG-rich region; a Cys2/Cys2-zinc finger motif and; a C-terminal RGG-rich region. Expression FUS is expressed in a housekeeping pattern.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -489- Localisation Nuclear, although FUS shuttles from the nucleus to the cytoplasm in a large complex that contains mRNA and hnRNPs. Function FUS is a RNA-binding protein that is identical to hnRNP P2 and may be implicated in mRNA metabolism. FUS seems to have a function as a heterogeneous ribonuclear protein (hnRNP)-like chaperone of RNA. In addition, it has been suggested that FUS might have a role in the BCR/ABL-mediated leukemogenesis. Homology FUS forms a sub-family of RNA binding proteins with EWS and RBP56/hTAFII68. FUS has homologous in mouse (fus), rat (pigpen) and Drosophila (Cabeza/SARFH). Mutations Germinal In the mouse, germline mutation in the fus gene produces male sterility, sensitivity to radiation, defective B-lymphocyte development and activation, chromosomal instability and perinatal death. Implicated in Note The FUS gene is implicated in several chromosomal translocations associated to both solid tumors and leukemias. The result of these chromosomal translocations are gene fusions. FUS contributes to these fusions with its N-terminal part, just before the RNA-binding domain. This domain confers to the fusion protein a transcriptional activation domain. These fusion genes generated as a result of chromosomal rearragements are used to monitor diagnosis and treatment.

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Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/ATF-1. Disease Angiomatoid fibrous histiocytoma (AFH). Hybrid/Mutated FUS was interrupted at codon 175 (exon 5) and fused to codon 110 Gene (exon 5) of ATF-1, resulting in an in-frame junction with a glycine to valine (GGT to GTT) transition.

Entity t(7;16)(q33;p11) chromosomal translocation. It produces the fusion protein FUS/CREB3L2 (also known as BBF2H7). Disease Low grade fibromyxoid sarcoma (LGFMS). Hybrid/Mutated The breakpoints in the fusion transcripts are produced between the Gene exons 6 or 7 of FUS and the exon 5 of CREB3L2.

Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3 (also known as CHOP). Disease Myxoid liposarcoma (MLS). Hybrid/Mutated 9 different types of fusions between the genes FUS and DDIT3 have

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -491- Gene been reported. The most frequent rearragements join the exons 5, 7 or 8 of FUS with the exon 2 of DDIT3. Oncogenesis The unequivocally relation between FUS/DDIT3 and the MLS was shown by the generation of a transgenic mouse model expressing FUS/DDIT3 from a housekeeping promoter.

Entity t(16;21)(p11;q22) chromosomal translocation. It produces the fusion protein FUS/ERG. Disease Acute myeloid leukemia (AML). Hybrid/Mutated The junction of both genes is produced between the exons 6 or 7 of Gene FUS and the exon 9 of ERG,or between the exon 8 of FUS and the exon 7 of ERG.

Breakpoints

External links Nomenclature Hugo FUS GDB FUS Entrez_Gene FUS 2521 fusion (involved in t(12;16) in malignant liposarcoma) Cards Atlas FUSID44 GeneCards FUS Ensembl FUS CancerGene FUS Genatlas FUS GeneLynx FUS eGenome FUS euGene 2521

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -492- Genomic and cartography FUS - 16p11.2 chr16:31098954-31110598 + 16p11.2 (hg17- GoldenPath May_2004) Ensembl FUS - 16p11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FUS Gene and transcription

Genbank AF071213 [ SRS ] AF071213 [ ENTREZ ]

Genbank AK098774 [ SRS ] AK098774 [ ENTREZ ]

Genbank AK130774 [ SRS ] AK130774 [ ENTREZ ]

Genbank BC000402 [ SRS ] BC000402 [ ENTREZ ]

Genbank BC002459 [ SRS ] BC002459 [ ENTREZ ]

RefSeq NM_001010850 [ SRS ] NM_001010850 [ ENTREZ ]

RefSeq NM_004960 [ SRS ] NM_004960 [ ENTREZ ]

RefSeq NT_086679 [ SRS ] NT_086679 [ ENTREZ ] AceView FUS AceView - NCBI TRASER FUS Traser - Stanford

Unigene Hs.513522 [ SRS ] Hs.513522 [ NCBI ] HS513522 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35637 [ SRS] P35637 [ EXPASY ] P35637 [ INTERPRO ]

Prosite PS50102 RRM [ SRS ] PS50102 RRM [ Expasy ]

Prosite PS01358 ZF_RANBP2_1 [ SRS ] PS01358 ZF_RANBP2_1 [ Expasy ]

Prosite PS50199 ZF_RANBP2_2 [ SRS ] PS50199 ZF_RANBP2_2 [ Expasy ]

Interpro IPR000504 RNA_rec_mot [ SRS ] IPR000504 RNA_rec_mot [ EBI ]

Interpro IPR001876 Znf_RanGDP [ SRS ] IPR001876 Znf_RanGDP [ EBI ] CluSTr P35637 Pfam PF00076 RRM_1 [ SRS ] PF00076 RRM_1 [ Sanger ] pfam00076 [ NCBI- CDD ] Pfam PF00641 zf-RanBP [ SRS ] PF00641 zf-RanBP [ Sanger ] pfam00641 [ NCBI-CDD ] Blocks P35637 Polymorphism : SNP, mutations, diseases OMIM 137070 [ map ] GENECLINICS 137070

SNP FUS [dbSNP-NCBI]

SNP NM_001010850 [SNP-NCI]

SNP NM_004960 [SNP-NCI]

SNP FUS [GeneSNPs - Utah] FUS [SNP - CSHL] FUS] [HGBASE - SRS]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -493- General knowledge Family FUS [UCSC Family Browser] Browser SOURCE NM_001010850 SOURCE NM_004960 SMD Hs.513522 SAGE Hs.513522 Amigo function|DNA binding Amigo function|RNA binding Amigo process|biological_process unknown Amigo component|nucleus Amigo function|protein binding Amigo function|zinc ion binding PubGene FUS Other databases Probes Probe FUS Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography

Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Crozat A, Aman P, Mandahl N, Ron D. Nature 1993 Jun 17; 363(6430): 640-644. Medline 8510758

An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Ichikawa H, Shimizu K, Hayashi Y, Ohki M.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -494- Cancer Res 1994 Jun 1; 54(11): 2865-2868. Medline 8187069

TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES. Oncogene 1994 Dec; 9(12): 3717-3729. Medline 7970732

Transcriptional activation by TAL1 and FUS-CHOP proteins expressed in acute malignancies as a result of chromosomal abnormalities. Sanchez-Garcia I, Rabbitts TH. Proc Natl Acad Sci U S A 1994 Aug 16; 91(17): 7869-7873. Medline 8058726

Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry. Calvio C, Neubauer G, Mann M, Lamond AI. RNA 1995 Sep; 1(7): 724-733. Medline 7585257

Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS. Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Hoglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F. Genomics 1996 Oct 1; 37(1): 1-8. Medline 8921363

Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript. Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M, Hayashi Y. Blood 1997 Aug 1; 90(3): 1192-1199. Medline 9242552

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -495- Oncogene 1997 Sep; 15(11): 1357-1362. Medline 9315104

A topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited. Zinszner H, Immanuel D, Yin Y, Liang FX, Ron D. Oncogene 1997 Jan 30; 14(4): 451-461. Medline 9053842

TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. Zinszner H, Sok J, Immanuel D, Yin Y, Ron D. J Cell Sci 1997 Aug; 110 ( Pt 15): 1741-1750. Medline 9264461

Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes. Morohoshi F, Ootsuka Y, Arai K, Ichikawa H, Mitani S, Munakata N, Ohki M. Gene 1998 Oct 23; 221(2): 191-198. Medline 9795213

TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis. Perrotti D, Bonatti S, Trotta R, Martinez R, Skorski T, Salomoni P, Grassilli E, Lozzo RV, Cooper DR, Calabretta B. EMBO J 1998 Aug 3; 17(15): 4442-4455. Medline 9687511

Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS). Ichikawa H, Shimizu K, Katsu R, Ohki M. Mol Cell Biol 1999 Nov; 19(11): 7639-7650. Medline 10523652

Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE. Nat Genet 2000 Feb; 24(2): 175-179. Medline 10655065

Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. Kuroda M, Sok J, Webb L, Baechtold H, Urano F, Yin Y, Chung P, de Rooij DG, Akhmedov A, Ashley T, Ron D. EMBO J 2000 Feb 1; 19(3): 453-462. Medline 10654943

A novel FUS/CHOP chimera in myxoid liposarcoma.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -496- Panagopoulos I, Mertens F, Isaksson M, Mandahl N. Biochem Biophys Res Commun 2000 Dec 29; 279(3): 838-845. Medline 11162437

Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Waters BL, Panagopoulos I, Allen EF. Cancer Genet Cytogenet 2000 Sep; 121(2): 109-116. Medline 11063792

Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma. Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, Mandahl N, Panagopoulos I. Hum Mol Genet 2003 Sep 15; 12(18): 2349-2358. Medline 12915480

The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Panagopoulos I, Tiziana Storlazzi C, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosjo O, Rydholm A, Isaksson M, Mandahl N, Mertens F. Genes Chromosomes Cancer 2004 Jul; 40(3): 218-228. Medline 15139001

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Atlas Genet Cytogenet Oncol Haematol 2004; 3 -497- Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- PA Pérez-Mancera, Isidro Sánchez-García 2004 Citation This paper should be referenced as such : Pérez-Mancera PA, Sánchez-García I. . FUS (fusion involved in t(12;16) in malignant liposarcoma). Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FUSID44.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -498- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Smad2, mothers against decapentaplegic homolog 2 (Drosophila)

Identity Other MADH2 names MADR2 JV18-1 JV18 Hugo SMAD2 Location 18q21.1 DNA/RNA Description The gene encompasses 90 kb of DNA; 12 exons. Transcription 2285 nucleotides mRNA. Alternative splicing was described. Protein

Description 467 amino acids; 52 kDa protein. A short 438 amino acids isoform was also described. Smad2 belongs to the Darfwin proteins family which are composed of two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively. Expression High expression levels in skeletal muscle, heart and placenta. Function Smad2 is an intracellular mediator of TGF-beta family and activin type 1 receptor. Smad2 mediate TGF-beta signaling to regulate cell growth and differentiation. Smad2 is released from cytoplasmic retention by TGF-beta receptor-mediated phosphorylation. The phosphorylated Smad2 then forms a heterodimeric complex with Smad4, and this complex translocates from cytoplasm into nucleus. By interacting with DNA-binding proteins, Smad complexes then positively or negatively regulate the transcription of target genes. Homology With the other members of the Darfwin/Smad family. Implicated in Disease Colorectal cancers Oncogenesis Smad2 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Inactivating mutations in Smad2 have been found in various cancer including colorectal carcinomas. The majority of tumor-derived mutations cluster in the carboxy-terminal MH2 domain, and some of these have been shown to disrupt TGF-beta

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -499- signaling by blocking receptor-dependent phosphorylation or by preventing heterodimeric interactions between Smads. A mutation at position 133 in the amino-terminal MH1 domain has also been associated with colorectal carcinoma. Nevertheless, loss of Smad2 activation and/or expression was related to occur in less than 10% of colorectal cancers.

To be noted Smad2 gene has also been found alterated in lung carcinomas, cervical carcinomas and hepatocellular carcinomas. External links Nomenclature Hugo SMAD2 GDB SMAD2 Entrez_Gene SMAD2 4087 SMAD, mothers against DPP homolog 2 (Drosophila) Cards Atlas SMAD2ID370 GeneCards SMAD2 Ensembl SMAD2 CancerGene MADH2 Genatlas SMAD2 GeneLynx SMAD2 eGenome SMAD2 euGene 4087 Genomic and cartography SMAD2 - 18q21.1 chr18:43618435-43711221 - 18q21.1 (hg17- GoldenPath May_2004) Ensembl SMAD2 - 18q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SMAD2 Gene and transcription

Genbank U78733 [ SRS ] U78733 [ ENTREZ ]

Genbank AA081871 [ SRS ] AA081871 [ ENTREZ ]

Genbank AA418737 [ SRS ] AA418737 [ ENTREZ ]

Genbank AF027964 [ SRS ] AF027964 [ ENTREZ ]

Genbank AI087928 [ SRS ] AI087928 [ ENTREZ ]

RefSeq NM_001003652 [ SRS ] NM_001003652 [ ENTREZ ]

RefSeq NM_005901 [ SRS ] NM_005901 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -500- RefSeq NT_086889 [ SRS ] NT_086889 [ ENTREZ ] AceView SMAD2 AceView - NCBI TRASER SMAD2 Traser - Stanford

Unigene Hs.465061 [ SRS ] Hs.465061 [ NCBI ] HS465061 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q15796 [ SRS] Q15796 [ EXPASY ] Q15796 [ INTERPRO ]

Interpro IPR001132 Dwarfin [ SRS ] IPR001132 Dwarfin [ EBI ]

Interpro IPR003619 Dwarfin_A [ SRS ] IPR003619 Dwarfin_A [ EBI ]

Interpro IPR008984 SMAD_FHA [ SRS ] IPR008984 SMAD_FHA [ EBI ] CluSTr Q15796

Pfam PF03165 MH1 [ SRS ] PF03165 MH1 [ Sanger ] pfam03165 [ NCBI-CDD ]

Pfam PF03166 MH2 [ SRS ] PF03166 MH2 [ Sanger ] pfam03166 [ NCBI-CDD ]

Smart SM00523 DWA [EMBL]

Smart SM00524 DWB [EMBL] Blocks Q15796

PDB 1DEV [ SRS ] 1DEV [ PdbSum ], 1DEV [ IMB ]

PDB 1KHX [ SRS ] 1KHX [ PdbSum ], 1KHX [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 601366 [ map ] GENECLINICS 601366

SNP SMAD2 [dbSNP-NCBI]

SNP NM_001003652 [SNP-NCI]

SNP NM_005901 [SNP-NCI]

SNP SMAD2 [GeneSNPs - Utah] SMAD2 [SNP - CSHL] SMAD2] [HGBASE - SRS] General knowledge Family SMAD2 [UCSC Family Browser] Browser SOURCE NM_001003652 SOURCE NM_005901 SMD Hs.465061 SAGE Hs.465061 Amigo component|nucleus Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent Amigo process|signal transduction BIOCARTA TGF beta signaling pathway PubGene SMAD2 Other databases

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -501- Probes Probe SMAD2 Related clones (RZPD - Berlin) PubMed PubMed 47 Pubmed reference(s) in LocusLink Bibliography A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway. Baker JC, Harland RM. Genes Dev 1996; 10: 1880-1889. Medline 8756346

MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Eppert K, Scherer SW, Ozczlik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L. Cell 1996; 86: 543-552. Medline 8752209

MADR2 is a substrate of the TGF-beta receptor and its phosphorylation is required for nuclear accumulation and signaling. Macias-Silva M, Abdollah S, Hoodless PA, Pirone R, Attisano L, Wrana JL. Cell 1996; 87: 1215-1216.

Mad-related genes in the human. Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Nat Genet 1996; 13: 347-349. Medline 8673135

Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers. Uchida K, Nagatake M, Osada H, Yatabe Y, Kondo M, Mitsudomi T, Masuda A, Takahashi T, Takahashi T. Cancer Res 1996; 56: 5583-5585. Medline 8971158

Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway. Nakao A, Roijer E, Imamura T, Souchelnytskyi S, Stenman G, Heldin CH, ten Dijke P. J Biol Chem 1997; 272: 2896-2900. Medline 9006934

Somatic alterations of the SMAD-2 gene in human colorectal cancers. Takagi Y, Koumura H, Futamura M, Aoki S, Ymaguchi K, Kida H, Tanemura H, Shimokawa K, Saji S.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -502- Brit J Cancer 1998; 78: 1152-1155. Medline 9820171

Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming growth factor-beta and activin signal transduction pathway. Takenoshita S, Mogi A, Nagashima M, Yang K, Yagi K, Hanyu A, Nagamachi Y, Miyazono K, Hagiwara K. Genomics 1998; 48: 1-11. Medline 9503010

Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers. Takenoshita S, Tani M, Mogi A, Nagashima M, Nagamachi Y, Benett WP, Hagiwara K, Harris CC, Yokota J. Carcinogenesis 1998; 19: 803-807. Medline 9635866

Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ. Cell 1998; 92: 797-808. Medline 9529255

Evidence that Smad2 is a tumor suppressor implicated in the control of cellular invasion. Prunier C, Mazars A, Noe V, Bruyneel E, Mareel M, Gespach C, Atfi A. J Biol Chem 1999; 274: 22919-22922. Medline 10438456

Smad2 and Smad4 gene mutations in hepatocellular carcinomas. Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Oncogene 1999; 18: 4879-4883. Medline 10490821

Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution. Funaba M, Mathews LS. Molec Endocr 2000; 14: 1583-1591. Medline 11043574

Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non- polyposis colorectal cancer. Roth S, Johansson M, Loukola A, Peltomaki P, Jarvinen H, Mecklin JP, Aaltonen LA. J Med Genet 2000; 37: 298-300. Medline 10819637

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -503-

Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Wu G, Chen YG, Ozdamar B, Gyuricza CA, Chong PA, Wrana JL, Massague J, Shi Y. Science 2000; 287: 92-97. Medline 11779503

Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Xu J, Attisano L. Proc Natl Acad Sci USA 2000; 97: 4820-4825. Medline 10781087

Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massague J, Shi Y. Mol Cell 2001; 8: 1277-1289. Medline 11779503

Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGF-beta signaling complexes in the cytoplasm and nucleus. Xu L, Kang Y, Col S, Massague J. Molec Cell 2002 ;10 : 271-282. Medline 12191473

Loss of expression, and mutations of Smad2 and Smad4 in human cervical cancer. Maliekal TT, Antony ML, Nair A, Paulmurugan R, Karunagaran D. Oncogene 2003; 31: 4889-4897. Medline 12894231

Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Xie W, Rim DL, Lin Y, Shih WJ, Reiss M. Cancer J 2003; 9: 302-312. Medline 12967141

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -504- 2004 Citation This paper should be referenced as such : Saffroy R, Antoinette Lemoine A, Debuire B . Smad2, mothers against decapentaplegic homolog 2 (Drosophila). Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SMAD2ID370.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -505- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(2;3)(p15-23;q26-27)

Identity Note There are 2 subtypes of the t(2p;3q); in one type the breakpoint on chromosome 2 is assigned to bands 2p21-23, whereas the breakpoint for the other type of breakpoint is localized at 2p15-21.

Partial GTG (Marian Stevens-Kroef, left) and RFA (Anne Hagemeijer, right) banded karyotypes of t(2;3)( p15-23;q26-27) with the distal (A) and proximal (B) breakpoint on chromosome 2.

Clinics and Pathology Disease In myeloid malignancies, (therapy-related) acute myeloid leukemias (AML), myelodysplastic syndromes (MDS) and chronic mylogenous leukemia in blastic crisis (CML-BC). Epidemiology 50 cases described so far; 4M/3F; age 3-80 years (median 52). Cytology Dysplastic bone marrow, dysmegakaryopoiesis, high platelet counts. Prognosis Poor prognosis: median survival 12 months (range 1-53). Cytogenetics Note Heterogeneous breakpoints by cytogenetic and FISH analysis; FISH mapping of 2p breakpoints was very heterogeneous; FISH mapping of the 3q breakpoint was within the EVI1-MDS region (between RP11- 694D5 (centromeric) and RP11-362K14 (telomeric) in the great majority of cases. Additional -7, del(7q), del(5q). The t(2p;3q) is also seen in t(9;22)(q34;q11) CML anomalies

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -506- Genes involved and Proteins Gene EVI1 Name Location 3q26 Note There is a direct correlation between mapping of the 3q breakpoint in the above given EVI1-MDS region and EVI1 ectopic expression by RT- PCR. Rare case with 3q break outside this interval failed to show ectopic expression of EVI1. Bibliography t(2;3)(p13;q26) in a case of chronic myeloid leukemia. Importance of the involvement of 3q26. Kwong YL, Chan LC, Lie KW. Cancer Genet Cytogenet 1992; 59(1): 95-96. Medline 1555200

Translocation (2;3)(p22;q28) is associated with myeloid disorders. Berger R, Flexor M, Le Coniat M, Derre J, Leblanc T. Cancer Genet Cytogenet 1995; 79(2): 130-132. Medline 7889504

Translocation (2;3)(p13;q26) in two cases of myeloid leukemia. Acute myeloblastic leukemia (M2) and blastic phase of chronic myeloid leukemia. Fleischman EW, Volkova MA, Frenkel MA, Konstantinova LN, Kulagina OE, Baranov AE, Gordeeva AA. Cancer Genet Cytogenet 1996, 87(2): 182-184. Medline 8625269 t(2;3)(p23;q26) in a patient with AML M2. Levaltier X, Penther D, Bastard C, Troussard X. Br. J. Haematol 1996; 92(4): 1027. Medline 8616064

Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: Report of 21 new cases, clinical, cytogenetic and molecular genetic features. Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij- Philipsen M, Geurts van Kessel A, Slater R, Hamers G, Michaux L, Speleman F, Hagemeijer A. Leukemia 2004; 18: 1108-1114. Medline 15085164

Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -507- Written 05- Marian Stevens-Kroef 2004

Citation This paper should be referenced as such : Stevens-Kroef M . t(2;3)(p15-23;q26-27). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0203p15q26ID1091.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -508- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Multiple myeloma

Clinics and Pathology Disease multiple myeloma (MM) is a malignant monoclonal plasma cell proliferation. Monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM) are premalignant states susceptible to transform in MM Phenotype / phenotype of mature terminally differenciated B-cell, but also with cell stem CD56 expression, which is not found in normal plasma cells; origin CD138+.CD38+ CD40+ Epidemiology multiple myeloma's annual incidence: 30/106; i.e. around 1% of malignancies in adults and 10% of haematologic malignancies; mean age: 62 yrs Clinics patients may be asymptomatic at the time of diagnosis; bone pain; susceptibility to infections; renal failure; neurologic dysfunctions Pathology MM staging: stage I: tumour cell mass < 0.6 X 1012/m2; Hb> 10 g/dl; serum calcium ¾ 120 mg/l; no bone lesion; low monoclonal Ig rate (IgG < 50 g/l, IgA < 30 g/l, BJ urine < 4 g/day); stage II: fitting neither stage I nor stage II; stage III: tumour cell mass > 1.2 X 1012/m2; Hb< 8.5 g/dl and/or serum calcium > 120 mg/l and/or advanced lytic bone lesions and/or high monoclonal Ig rate (IgG > 70 g/l, IgA > 50 g/l, BJ urine > 12 g/day) Treatment none before onset of symptoms; chemotherapy or BMT afterwards. Various new therapies, mainly acting by apoptosis induction in MM cells, are or will be involved in clinical trails (thalidomide, proteasome inhibitor PS-341, 2 methoxy estradiol, arsenic trioxyde, TNF alpha). Prognosis evolution: multiple myeloma can evolve towards plasma cell leukemia, where plasma cell count is greater than 2000/ mm3; survival is highly variable (median is around 3 yrs); prognosis is according to the staging and other parameters (such as age, serum albumin, b2 microglobulin, C-reactive protein, and plasma cell labeling index); the karyotype is emerging as an important prognostic factor: median survival in case of a normal karyotype could be 4 yrs vs 1 yr in case of -13/del(13q) and/or 11q rearrangements (the chromosome anomalies with the worst prognostic impact) Cytogenetics Cytogenetics cytogenetic information is limited, as the malignant cells have a low Morphological spontaneous proliferative activity; abnormal karyotypes are found in 30-50% of cases, more often in advanced stages than in newly

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -509- diagnosed patients (is this because chromosome abnormalities are secondary events, or because malignant cells have an increased proliferative activity in advanced stages: see below); karyotypes are complex; hyperploidy is found in 2/3 of cases; karyotypes may evolve from normal to abnormal during course of the disease; - structural (and variable) anomalies of chromosome 1 are found in 30-40% of cases, 14q rearrangements in 25% of cases, 11q abnormalities in 20 %, t(11;14)(q13;q32) representing 10%; 6q anomalies represent 15% of cases; FISH is indicated, as metaphases are arduous to obtain in such a disease implicating mature cells, and tend to show that most cases bear chromosome anomalies, irrespective of the disease staging. Cytogenetics All MM cells should express chromosome abnormalities, as strongly Molecular suggested by interphase FISH and CGH. Aneuploidy is detected in 67-90% of cases, allowing to define 2 prognosis entities: 1) hyperdiploid sub-group with a significantly better overall survival, gains involving primarily +3, +5, +7, +9, +11, +15, +19, +21 and infrequent structural abnormalities. 2) hypodiploid group (+hypotetraploid cases by endoreduplication of a prior hypodiploid karyotype) strongly correlated with complex structural rearrangements, 14q32 translocations, del(13q)/-13 and a more aggressive evolution. IG rearrangements: translocations involving 14q32 are found in at least 65-70% of patients, most of them result from short segments exchange and are detected quite exclusively by FISH. Five translocations involving IGH locus are particularly relevant and considered as very early primary events: t(4;11)(p16;q32), t(6;14)(p25;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), t(14;20)(q32;q11). Other translocations involving IGH are rare or sporadic, they should be secondary and not mediated by specific recombination mechanisms. Del13q/-13: 13q14.3 deletions emerge as a major independant pronostic factor, underevaluated by conventional cytogenetics; found by FISH in 20-30% of patients; associated with a significant lower rate of response to conventional chemotherapy, and to a shorter survival. Genes involved and Proteins Gene FGFR3 Name Location 4p16 Note Involved in t(4;14)(p16;q32), approximately 15% of MM cases. FGFR3 (tyrosine kinase receptor) and MMSET (novel gene homologous to a Drosophila dysmorphy gene, see below)) are in opposite transcriptional orientation at 4p16. Both are involved in t(4;14). The translocation generates 2 fusion genes, IGH-MMSET on der(4) and FGFR3-IGH on der(14).

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -510- Gene WHSC1 (MMSET) Name Location 4p16 Note involved in t(4;14)(p16;q32) (see above) Gene CCND3 (Cyclin D3) Name Location 6p21 Note Involved in t(6;14)(p21;q32) (3-5% of MM cases). Detected quasi exclusively by FISH. Gene BCL1 Name Location 11q13 Note BCL1 (also called Cyclin D1 or CCND1) is involved in t(11;14) )(q13;q32) cases. Approximately 15-20% of cases. Same translocation as mantle cell lymphoma but IGH breakpoint different (IGHS vs IGHJ) Gene MAF Name Location 16q23 Note basic zipper transcription factor, involved in t(14;16)(q32;q23) (5% of MM cases). Detected quasi exclusively by FISH Gene MAFB Name Location 20q11 Note MAF family basic region / leucine zipper transcription factor, involved in t(14;20)(q32;q11) (2% of MM cases) Gene C-MYC Name Location 8q24 Note Overexpression (mainly without rearrangement or amplification) correlated with increased tumour cell burden. RAS mutations (found in 20% of cases) and P53 mutations are associated with advanced disease Gene RB1 Name Location 13q14 Note RB1is deleted in more than 1/3 of cases. 13q14.3 deletions have been observed without RB1 loss, which should mean that RB1 is not the only critical locus of 13q14.3 sub-band. D13S25 and D13S319 appear as the more commonly deleted loci. Bibliography Multiple myeloma and chronic lymphocytic leukemia. Rosen L, Vescio R, Berenson JR

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -511- Curr Opin Hematol. 1995 Jul;2(4):275-82. Review Medline 98039277

Cytogenetics and molecular genetics in multiple myeloma. Feinman R, Sawyer J, Hardin J, Tricot G Hematol Oncol Clin North Am. 1997 Feb;11(1):1-25. Review Medline 97236322

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations. Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Sole F, Cuesta B, Gullon A. Genes Chromosomes Cancer. 1997; 18: 84-93. Medline 9115968

Hypodiploidy is a major prognostic factor in multiple myeloma. Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C; Groupe Francais de Cytogenetique Hematologique. Blood. 2001; 98: 2229-2238. Medline 11568011

Clinical and biologic implications of recurrent genomic aberrations in myeloma. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, Dewald GW, Van Ness B, Van Wier Blood. 2003; 101: 4569-4575. Medline 12576322

Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results. Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A, Osier DG, Orchard KH. Br J Haematol. 2003; 120: 944-952. Medline 12648063

Advances in Biology of Multiple Myeloma: Clinical Applications. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Blood. 2004 Apr 15 Medline 15090448

Genetics and cytogenetics of multiple myeloma: a workshop report. Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H. Cancer Res. 2004; 64: 1546-1558. Medline 14989251

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -512-

Contributor(s) Written 01- Jean-Loup Huret 1998 Updated 06- Franck Viguié 2004 Citation This paper should be referenced as such : Huret JL . Multiple myeloma. Atlas Genet Cytogenet Oncol Haematol. January 1998 . URL : http://AtlasGeneticsOncology.org/Anomalies/MMULID2038.html Viguié F . Multiple myeloma. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://AtlasGeneticsOncology.org/Anomalies/MMULID2038.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

Polyclonal B Lymphocytosis with Binucleated Lymphocytes (PPBL)

Clinics and Pathology Phenotype / Unknown. The polyclonal expansion of B-cells fit into the peripheral cell stem CD27+IgM+IgD+ B cell population. Cloning and sequencing of VH origin genes of PPBL IgVH genes showed a mutated profile suggesting like CD27 expression an expansion of memory B cells. Etiology The etiology of polyclonal B lymphocytosis with binucleated lymphocytes (PPBL) remains unknown. An association with cigarette smoking was initially suggested. However PPBL was observed in non smokers patients. The morphology of binucleated lymphoid B-cells could suggest an association with viral infections, such as Epstein-Barr Virus. Biologic studies are not completely achieved to exclude and/or to confirm definitely the role of EBV in the pathogenesis of PPBL. The presence of characteristic binucleated lymphoid B-cells in asymptomatic family members and the description of familial PPBL cases suggest a genetic predisposition as a more likely possibility. Epidemiology PPBL was first reported in 1982. We have no epidemiological data on the incidence of PPBL. Clinics In a large series we reported on forty-three patients (9 males, 34 females: median age: 40 years, range 28-65), the clinical characteristics were splenomegaly in 16%, hepatomegaly in 0.5% and lymph nodes in 11.5% cases. An absolute lymphocytosis > 4 x 109/l is present in 80% of PPBL patients. A persistent, stable and polyclonal increase of IgM levels is usual and most PPBL patients express HLA- DR7. CYTOLOGY_IMAGE lymphocytosisFig1.jpg Cytology PPBL is identified in all cases by the presence of a variable (1.5 to 9%) number of binucleated peripheral lymphoid cells (Fig 1). The majority of lymphoid cells are large with abundant faintly and basophilic cytoplasm. Characteristic nuclei with a rounded or more commonly irregular form are observed. Immunologic markers: Both kappa and lambda light-chain are expressed, indicating a polyclonal expansion of the lymphocyte pool. The lymphocytosis is of the B-cell type: the lymphocytes react with CD19, CD20, CD22 and FMC7 antigens. Morphologic features showing typical binucleated cells

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -514- Prognosis After a median follow-up of 5.5 years without treatment, 45 PPBL patients are alive. Cytogenetics Cytogenetics +i(3q) (Fig 2) is the most common abnormality and is observed in 70% Morphological cases, occurring as a single aberration in only a few patients. PCC (Fig 3) is observed in 40% cases and occur rarely as a sole abnormality. Both abnormalities associating +i(3q) and PCC are present in 37% cases. Using alpha-satellite and telomere chromosome 3 specific probes, +i(3q) is more frequently detected by metaphase FISH studies. (Fig 2). +i(3q) is rarely described as a recurrent cytogenetic abnormality in patients with hematologic malignancy. Trisomy 3 is reported to be associated with marginal zone B-cell lymphoma. Gain of chromosome 3 or 3q was described in patients with typical clonal b-cell chronic lymphoproliferative disorders, chronic lymphocytic leukemia, prolymphocytic leukemia or Waldenström macroglobulinemia. A chromosomal instability is present in 67.5% patients These patients present various clonal [ del(6q), +der(8) or +8 or polyploid karyotype] and non clonal chromosomal abnormalities with structural and numerical abnormalities. This chromosomal instability is variable over time but persist in most cases. In spite of genomic instability, a long follow-up of PPBL patients remains essential and chemotherapy unnecessary.

Partial karyotype showing +i(3q) -R-banding (left); Detection of I(3q) with telomere chromosome 3q and alpha satellite specific DNA probes (right)

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -515-

Premature Chromosome Condensation (PCC)

Bibliography Persistent polyclonal lymphocytosis of B-lymphocytes. Gordon DS, Jones BM, Browing SW, Spira TJ, Laurence DN. New Engl J Med 1982; 307: 232-236.

Chronic B-cell lymphocytosis of the young woman : clinical, phenotypic, and molecular studies. Delage B, Darveau A, Jacques L, Huot A, Delage JM Blood, 1992, 80, suppl 1, 447a.

Polyclonal lymphocytosis with binucleated lymphocytes: a genetic predisposition. Troussard X, Valensi F, Debert C, Maydanie M, Schillinger F, Bonnet P, MacIntyre E, Flandrin G. Brit J Haematol 1994; 88: 275-280.

Persistent polyclonal B-cell lymphocytosis is an expansion of functional IgD+CD27+ memory B-cells. Himmelmann A, Gautschi O, Nawrath M, Bolliger u, Fehr J, Stahel RA. Brit J Haematol 2001, 114, 400-405.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -516- Analysis of expressed VH genes in persistent polyclonal B cell lymphocytosis reveals absence of selection in CD27+IgM+IGD+ memory B cells. Loembe MM, Néron S, Delage R, Darveau A. Eur J Immunol 2002; 32: 3678-3688.

Chromosomal instability and ATR Amplification Gene in Patients with persistent and polyclonal B-Cell Lymphocytosis (PPBL). H. Mossafa, S. Tapia, G. Flandrin, X. Troussard and the Groupe Français d¹Hématologie Cellulaire (GFHC). Leukemia Lymphoma 2004; 45: 1401-1406.

Contributor(s) Written 06- Xavier Troussard, Hossein Mossafa 2004 Citation This paper should be referenced as such : Troussard X, Mossafa H . Polyclonal B Lymphocytosis with Binucleated Lymphocytes (PPBL). Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/PolyclonalLymphoID2040.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -517- Atlas of Genetics and Cytogenetics in Oncology and Haematology

+6 or trisomy 6

Clinics and Pathology Note Trisomy 6 (+6) has been reported as the sole cytogenetics aberration in 14 cases of acute myeloid leukaemia (AML) and five cases of myelodysplastic syndrome. Three out of four AML patients with +6 in one series showed AML-M1 morphology and expression of stem cell antigen CD34 on the leukaemic blasts, suggesting that +6 may be associated with a more primitive form of AML. Nevertheless, other reported cases represent a broader spectrum of AML and it is therefore premature to draw conclusion as to whether special morphological and phenotypic features exist in AML with +6.

Intriguingly, +6 as the sole cytogenetics abnormality have been reported in 12 cases of haematological disorders characterized by peripheral blood cytopenia and hypoplastic bone marrow. Among the 12 cases, eight cases showed dysplastic change in the haemopoietic cells, whereas four did not. In two cases of aplastic anaemia with dyserythropoiesis and +6, FISH showed +6 in erythroid as well as myeloid cells, suggesting involvement of an early haemopoietic progenitor cell. The overall survival ranges from 9 - 48 months. In all cases, normal cells without +6 are present, and the percentage of metaphases with +6 ranges from 6.9% to 85%. It is questionable whether such cases should be classified as hypoplastic MDS, based on clonal cytogenetic change of +6, or aplastic anaemia. The pathogenesis of aplastic anaemia is heterogeneous. While an immunological basis for this disorder is established based on response to immunosuppressive therapy, there is also evidence for clonal nature resulting from damage to the haemopoietic stem cell compartment. Indeed clonal chromosomal abnormalities are reported in otherwise typical aplastic anaemia. Furthermore, aplastic anaemia evolving into acute leukaemia is well documented. This is exemplified by the development of AML in a case of aplastic anaemia with +6 and no dysplasia 15 months after initial diagnosis. Although patients with +6 and marrow aplasia were uniformly non-responsive to treatments by steroids and anti-thymocyte globulin (ATG), clinical response to cyclosporine was seen in two cases. There was improvement of platelet count in one case and complete clinical response in another. Taken together, it is plausible that +6 defines a distinctive subtype of aplastic anaemia with mild dysplastic changes, poor response to steroids and ATG therapy, and a propensity for AML transformation.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -518- Rare instances of +6 may be encountered in childhood acute mixed lineage leukaemia, lymphoblastic transformation of chronic myeloid leukaemia, and chronic myeloproliferative disorder. Phenotype / Three out of four AML patients with +6 in one series showed AML-M1 cell stem morphology and expression of stem cell antigen CD34 on the leukaemic origin blasts, suggesting that +6 may be associated with a more primitive form of AML. Evolution A case of aplastic anaemia with +6 and no dysplasia showed transformation into AML at 15 months after initial diagnosis. Prognosis Trisomy 6 may define a distinctive subtype of aplastic anaemia with mild dysplastic changes, poor response to steroids and ATG therapy, and a propensity for AML transformation. More cases need to be collected to substantiate this contention. Cytogenetics

Complete karyotype showing 47,XY,+6. G-banding with trypsin/Giemsa. The patient is an 81-year old Chinese man who was admitted for myocardial infarction and was found to be anaemic. Physical examination was unremarkable. Blood counts showed: haemoglobin 8.6 g/dL, white cell count 3.2 X 109/L, and platelet count 174 X 109/L. Bone marrow morphology, cytochemistry and immunophenotyping results were consistent with a diagnosis of acute myeloid leukaemia. Chromosome analysis on bone marrow cells showed: 47,XY,+6[2]/46,XY[5].

External links Other +6 or trisomy 6 Mitelman database (CGAP - NCBI) database Bibliography Trisomy 6 associated with aplastic anemia. Geraedts JP, Haak HL. Hum Genet 1976; 35: 113-115. Medline 1002160

Correlation between prognosis and bone marrow chromosomal patterns in children with acute nonlymphocytic leukemia: similarities and differences compared to adults. Benedict WF, Lange M, Greene J, Derencsenyi A, Alfi OS. Blood 1979; 54: 818-823. Medline 289424

Chromosome aberrations and prognosis in preleukaemia. Panani A, Papayannis AG, Sioula E.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -519- Scand J Haematol 1980; 24: 97-100. Medline 6929565

Chromosomal alterations in acute leukemia patients studied with improved culture methods. Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH. Cancer Res 1985; 45: 430-434. Medline 3855285

Multiple chromosomally distinct cell populations in myelodysplastic syndromes and their possible significance in the evolution of the disease. Mecucci C, Rege-Cambrin G, Michaux JL, Tricot G, Van den Berghe H. Br J Haematol 1986; 64: 699-706. Medline 3801319

Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia. Appelbaum FR, Barrall J, Storb R, Ramberg R, Doney K, Sale GE, Thomas ED. Exp Hematol 1987; 15: 1134-1139. Medline 3315724

Prognostic significance of chromosome analysis in de novo acute myeloid leukemia (AML). Weh HJ, Kuse R, Hoffmann R, Seeger D, Suciu S, Kabisch H, Ritter J, Hossfeld DK. Blut 1988; 56: 19-26. Medline 3422167

Trisomy 6: a recurring cytogenetic abnormality associated with marrow hypoplasia. Moormeier JA, Rubin CM, Le Beau MM, Vardiman JW, Larson RA, Winter JN. Blood 1991; 77: 1397-1398. Medline 2001462

Cytogenetic analysis of hematologic malignancies in Hong Kong. A study of 98 cases. Chan LC, Kwong YL, Liu HW, Chan TK, Todd D, Ching LM. Cancer Genet Cytogenet 1992; 62: 154-159. Medline 1394102

Trisomy 6 as the sole chromosome abnormality in myeloid disorders. Jonveaux P, Fenaux P, Berger R. Cancer Genet Cytogenet 1994; 74: 150-152. Medline 8019961

Primary, single, autosomal trisomies associated with haematological disorders.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -520- United Kingdom Cancer Cytogenetics Group (UKCCG). Leuk Res 1996; 16: 841-851. Medline 1405715

Trisomy 6 is the hallmark of a dysplastic clone in bone marrow aplasia. La Starza R, Matteucci C, Crescenzi B, Criel A, Selleslag D, Martelli MF, Van den Berghe H, Mecucci C. Cancer Genet Cytogenet 1998; 105: 55-59. Medline 9689931

Trisomy 6 as a primary karyotypic aberration in hematologic disorders. Mohamed AN, Varterasian ML, Dobin SM, McConnell TS, Wolman SR, Rankin C, Willman CL, Head DR, Slovak ML. Cancer Genet Cytogenet 1998; 106: 152-155. Medline 9797781

Trisomy 6 in a childhood acute mixed lineage leukemia. Onodera N, Nakahata T, Tanaka H, Ito R, Honda T. Acta Paediatr Jpn 1998; 40: 616-620. Medline 9893302

Trisomy 6 and double minute chromosomes in a case of chronic myelomonocytic leukemia. Sambani C, Trafalis DT, Vessalas G, Politis G, Peristeris P, Nakopoulou L, Giannopoulou J, Michaelidis C, Ayoutantis M, Pantelias GE. Cancer Genet Cytogenet 1998; 106: 180-181. Medline 9797788

Trisomy 6 acquired in lymphoid blast transformation of chronic myelocytic leukemia with t(9;22). Yilmaz Y, Klein R, Qumsiyeh MB. Cancer Genet Cytogenet 2003; 145: 86-87. Medline 12885470

A rapidly progressive chronic myeloproliferative disease with isolated trisomy 6. Wong KF. Cancer Genet Cytogenet 2004; 149: 176-177. Medline 15036897

Contributor(s) Written 06- Edmond SK Ma, Thomas SK Wan 2004 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -521- Ma ESK, Wan TSK . +6 or trisomy 6. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tri6ID1013.html

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Bone: Aneurysmal bone cysts

Clinics and Pathology Etiology The most widely accepted pathogenetic mechanism of aneurysmal bone cysts involves a local circulatory disturbance leading to markedly increased venous pressure and the development of a dilated and enlarged vascular bed within the affected bone area. However, the recent identification of recurrent chromosome abnormalities has challenged this historical perception. Clinics Aneurysmal bone cysts (ABC) are benign lesions that occur more frequently in the metaphyses of long bones, especially distal femur, the proximal tibia and vertebral posterior bodies. It can occur at any age but most patients are diagnosed in the first 2 decades of life. It can exist as primary bone lesion or as secondary lesions arising in association with other osseous conditions, namely giant cell tumor, chondroblastoma, chondromyxoid fibroma and fibrous dysplasia. Pain and swelling are the most common complaints. Pathology As the name implies, the lesion is histopathologically characterized by hemorrhagic cystic and cavernous spaces surrounded by fibrous septa composed of mildly to moderately mitotically active spindle cells intermixed with scattered osteoclast-like multinucleated giant cells. Approximately 95% of ABC have typical histology whereas the remaining 5% are "solid" variants in which the usual cavernous channels and spaces may not be identified. An extraosseous couterpart of ABC has been described, sometimes referred to as ABC of soft tissues, and is histologically identical to ABC but diagnosed much less frequently. Treatment ABC is most frequently treated by curettage, but local recurrences can still occur in a substantial number of cases. Cytogenetics Cytogenetics Chromosome bands 16q22 and/or 17p13 are non randomly Morphological rearranged in ABC, regardless of tumor type (classic, solid) and or location (osseous and extraosseous). A recurrent t(16;17)(q22;p13) has been identified, but other chromosomal segments as translocation partner for each chromosome have been described: t(1;17)(p34;p13) THRAP3 -USP6, t(3;17)(q21;p13) ZNF9 -USP6, t(9;17)(q22;p13) OMD -USP6, t(17;17)(q12;p13) COL1A1 -USP6 Although additional cases should be studied, it appears that in combined giant cell tumor and secondary aneurysmal bone cyst, both lesions can retain their characteristic chromosomal aberrations.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -523- Genes involved and Proteins Gene USP6 (Ubiquitin Specific Protease 6). Also known as TRE-2 or TRE17. Name Location 17p13 Dna / Rna 7878 bp (major transcript) Protein 786 amino acids; USP6 is a hominoid-specific gene that was initially cloned form an Ewing sarcoma cell line. It arose from an evolutionary chimeric gene fusion between the TBC1D3 (also known as PRC17) and USP32 (NY-REN-60) genes, which are both located on the long arm of chromosome 17. Sequence comparisons indicate that the first 14 exons of USP6 are derived from TBC1D3(PRC17) whereas exons 15 to 30 are derived from USP32(10). TBC1D3(PRC17) is located at chromosome band 17q12 and encodes a protein with a TBC/GAP domain involved in Rab/Ypt GTPase signaling. USP32 is located at chromosome band 17q23 and encodes a protein composed of two EF-hand calcium- binding motifs, a myristoylation site, and a UBP domain. USP6 protein retains the TBC domain of TBC1D3 (PRC17) and the UBP domain of USP32. Because USP6 is absent in non-hominoid primates and is primarily expressed in testicular tissue, it has been suggested that USP6 contributed to hominoid speciation. Until recently USP6 function was poorly know but recent data suggest that USP6 is a component of a novel effector pathway for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling.

Gene CDH11 (Cadherin 11 or Osteoblast Cadherin or OB-Cadherin) Name Location 16q21-q22.1 Dna / Rna 3.6 and 3.8 kb mRNA (two major transcripts) Protein 693 and 796 amino acids; Membrane protein that mediate calcium- dependent cell-cell adhesion, member of the cadherin superfamily. CDH11 seems to be highly expressed during the development and differentiation of the osteoblastic lineage, indicating an important role in bone development. Two splice variants have been identified, one of which encodes an isoform with a shorter cytoplasmic domain.

Result of the chromosomal anomaly Hybrid Gene Description 5 Œ CDH11- 3 Œ USP6 Fusion

Protein Description Fusion of the promoter region of CDH11 (noncoding exons 1 and 2) to

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -524- the entire coding region of USP6, which starts on exon 2. Therefore, there is only a fusion gene but not a fusion protein. This type of gene fusion is known as promoter swapping and has been described in other solid tumors, including pleomorphic adenoma and lipoblastoma. Oncogenesis The oncogenic mechanism of CDH11-USP6 is still unknown but very likely involves transcription upregulation of USP6 mediated by the highly active CDH11 promoter.

Bibliography Cytogenetic findings in aneurysmal bone cysts. Pfeifer FM, Bridge JA, Neff JR, Mouron BJ. Genes Chromosomes Cancer 1991; 3: 416-419.

Solid variant of aneurysmal bone cyst. Bertoni F, Bacchini P, Capanna R, Ruggier, P, Biagini R, Ferruzzi A, Bettelli G, Picci P, Campanacci M. Cancer 1993; 71: 729-734. Medline 8431852

Primary aneurysmal cyst of soft tissues (extraosseous aneurysmal cyst). Rodriguez-Peralto J L, Lopez-Barea F, Sanchez-Herrera S, Atienza M. Am J Surg Pathol 1994; 18: 632-636.

Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cysts.. Dal Cin P, Kozakewich HP, Goumnerova L, Mankin HJ, Rosenberg AE, Fletcher JA. Genes Chromosomes Cancer 2000; 28: 233-234. Medline 10825009

Cytogenetic analysis of aneurysmal bone cyst, giant cell tumor of bone and mixed lesions. A report from the CHAMP study group. Sciot R , Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CDM, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai R, Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R,Willén H. Modern Pathol 2000; 13: 1206-1210 Medline 11106078

Aneurysmal bone cysts with chromosomal changes involving 7q and 16p. Baruffi,MR,Neto JB,Barbieri CH, Casartelli C. Cancer Genet Cytogenet 2001; 129: 177-180. Medline 11566352

Translocation (16;17)(q22;p13) is a recurrent anomaly of aneurysmal bone cysts Herens C, Thiry A, Dress MF, Born J, Flagothier C, Vanstraelen G, Allington N, Bex

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -525- V. Cancer Genet Cytogenet 2001; 127: 83-84 Medline 11408073

Soft tissue aneurysmal bone cyst. A clinicopathologic study of five cases. Nielsen GP, Fletcher CDM, Smith MA, Rybak L, Rosenberg AE. Am J Surg Pathol 2001; 26: 64-69.

Primary aneurysmal bone cysts: 16q22 and /or 17p13 chromosome abnormalities. Wyatt-Ashmead J, Bao L, Eilert RE, Gibbs P, Glancy G, McGvran L. Pediatric Dev Pathol 2001; 4: 418-419.

Aneurysmal bone cyst of the nose with 17p13 involvement. Winnepenninckx V, Debiec-Rychter M, Jorissen M, Bogaerts S, Sciot R. Virchows Arch. 2001;439(5):636-9.

Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization Althof PA, Ohmori K, Zhou M, Bailey JM, Bridge RS, Nelson M, Neff JR, Bridge JA. Mod Pathol. 2004 May;17(5):518-25.

USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Oliveira AM, Hsi BL, Weremowicz S, Rosenberg AE, Dal Cin P, Joseph N, Bridge JA, Perez-Atayde AR, Fletcher JA. Cancer Res. 2004;64(6):1920-3.

World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue Tumor and Bone. Aneurysmal bone cyst 338-339 Fletcher CDM, Unni KK, Mertens F IARC Press: Lyon 2002

USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F, Derr V, Hsi BL, Gebhardt MC, Rosenberg AE, Fletcher JA. Am J Pathol 2004; 165: 1773-1780. Medline 15509545

Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oliveira AM, Perez-Atayde AR, Dal Cin P, Gebhardt MC, Chen CJ, Neff JR, Demetri GD, Rosenberg AE, Bridge JA, Fletcher JA. Oncogene 2005 [Epub ahead of print] Medline 15735689

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -526- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

Contributor(s) Written 01- Paola Dal Cin 2002 Updated 06- Paola Dal Cin 2004 Citation This paper should be referenced as such : Dal Cin P . Bone: Aneurysmal bone cysts. Atlas Genet Cytogenet Oncol Haematol. January 2002 . URL : http://AtlasGeneticsOncology.org/Tumors/AneurBoneCystID5133.html Dal Cin P . Bone: Aneurysmal bone cysts. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/AneurBoneCystID5133.html

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -527- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Lung: small cell cancer

Classification Note Although it is possible to distinguish a number of different histological sub-classes of lung cancer by light microscopy, the most important current clinical distinction is between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Based primarily on its clinical behaviour, SCLC, a neuroendocrine lesion, is considered as a separate entity to the non-small cell carcinomas. The disease has a particularly aggressive clinical course with widespread early metastasis and somewhat in contrast to NSCLC, tumours will frequently show a short term response to cytotoxic chemotherapy and radiotherapy. As SCLC is almost always overtly metastatic at presentation, surgical resection is rare. Clinics and Pathology Note Small cell carcinomas tend to be centrally located, arising in a large bronchus, with only a small number presenting as peripheral lesions. The tumours generally grow around the bronchus, invading surrounding structures. They may obstruct the airway, but this is generally through circumferential compression rather than luminal invasion. Extensive necrosis and lymph node metastases are common.

SCLC cells are small and round to fusiform with scant cytoplasm. The relatively large round, oval or fusiform nucleus contains finely stippled chromatin and nucleoli may be inconspicuous or absent. The tumour cells, which have a high mitotic index, often grow in sheets but they may be arranged in ribbons or rosettes. Small cell carcinomas frequently express markers of neuroendocrine differentiation such as creatine kinase-BB, chromogranin and neuron specific enolase. They may also express small peptide hormones such as gastrin-releasing peptide, calcitonin and serotonin. As significant differences exist in the treatment of SCLC and NSCLC, the distinction of SCLC from other neuroendocrine lesions (such as large cell neuroendocrine carcinoma) is important. No pre-malignant states have been identified for small cell tumours.

Although in the future, gene expression profiling is likely to define new disease subdivisions with variable drug sensitivities and outcomes, only two subtypes of SCLC are currently discriminated:

small cell carcinoma (about 90%);

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -528- combined small cell carcinoma (about 10%) It is not clear whether this division is clinically significant, but it may be taken into account when therapy is considered. In the combined tumour, SCLC may be mixed with a second histological component of NSCLC (large cell, adenocarcinoma or squamous cell) and the relative balance of the subtypes within the tumour may shift after chemotherapy. Such observations lend weight to the argument for a common stem cell origin of lung tumours, a hypothesis supported by microarray data which suggest that small cell tumour gene expression patterns are closely related to those of bronchial epithelial cells. Staging Using molecular analyses, malignant cells can be demonstrated at distant sites in all cases of diagnosed SCLC and patients should therefore receive combination chemotherapy as part of their treatment. Staging of the disease, although not carried out in order to identify a subset of patients who might be treated with local therapy, is nevertheless useful to direct treatment and predict prognosis. Bronchoscopy usually allows biopsy of the primary tumour which defines the diagnosis but if malignant small cells are detected cytologically in the sputum, this may be unnecessary. Appropriate subsequent investigations include: clinical examination, blood analyses including haemoglobin, leukocyte, thrombocyte counts, assessment of liver and kidney function and measurement of electrolytes (sodium, calcium), uric acid, alkaline phosphatase, and lactate dehydrogenase (LDH). Further investigations may include: bone scan (if there are bone pains, elevated calcium or alkaline phosphatase), thoracic and abdominal CT scan and in the case of a pathological neurological status, an MRI or CT scan of the brain. Nowadays, bone marrow punctures are indicated in rare situations only. These examinations allow a two stage classification of limited versus extensive disease. Limited disease is defined as a tumour confined to the hemithorax of origin and regional lymph nodes that can be encompassed in a tolerable radiation therapy port (20-30% of patients). Beyond this, the tumour is classified as an extensive disease (60-70% of patients). The most important prognostic factors are tumour extent (extensive disease), performance status, elevated LDH and alkaline phosphatase, and decreased sodium level (Manchester Score). Cure is rare even in limited disease (10%); disease-free survivals at 2 years are 30% and 3% for limited and extensive disease, respectively. Treatment SCLC is highly sensitive to chemotherapy. Response rates vary between 50-90% depending on the stage of disease and the patient's tolerance of the chemotherapy. Survival and quality of life are generally highly improved. In extensive disease, several (up to six) cycles of a platinum containing combination therapy is usually administered. In

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -529- case of relapse further chemotherapy is given with less success, but even in this situation, quality of life might be improved. In limited disease, combination chemotherapy concomitantly with radiotherapy is the cornerstone of management. In the case of complete remission, initial therapy is completed by a prophylactic cranial irradiation. Cytogenetics Note As surgical resection is rare, and although some primary tumour karyotypes have been reported, much of the information on cyctogenetic abnormalities in SCLC is based on the analysis of short term cultures and cell lines. Chromosomal changes are usually fairly extensive. Although no characteristic balanced translocations have been identified, breakpoints tend to cluster on chromosomes 1, 3, 5 and 17. Losses of the short arms of chromosome 3 and 17 and the long arm of 5 are seen consistently.

In addition to these changes, extra-chromosomal double minutes and intra-chromosomal homogeneously staining regions have sometimes been observed, especially in SCLC cell lines and especially in tumours from chemotherapy-treated patients. These characteristic structures, indicative of somatic gene amplification, generally encode multiple copies of MYC family genes.

Comparative genomic hybridisation (CGH) has been used to extend conventional karyotypic analysis in SCLC. Prominent imbalances seen in several studies include losses of chromosomes 3, 4, 5, 8, 10, 13 and 17 with the most frequently implicated regions being 3p13-14, 4q32-35, 5q32-35, 8p21-22, 10q25, 13q13-14 and 17p12-13. Common gains include 3q, 5p, 8q and 19q with the most commonly involved sub- regions being 3q26-29, 5p12-13, 8q23-24 and 19q13.1.

Using molecular probes, the loss of material from the short arm of chromosome 3 has been shown to occur in almost 100% of SCLCs. This striking loss may occur in the earliest stages of malignancy: in histologically normal and pre-neoplastic smoking damaged epithelia. A number of different regions of 3p have subsequently been highlighted by high density allelotyping leading to the hypothesis that multiple tumour suppressor genes involved in lung cancer pathogenesis may be localised to 3p. Whilst many candidates have been considered (including FHIT, RASSF1 and FUS1) none show consistent coding sequence mutation in SCLC. However, a number of these candidate sequences show epigenetic differences between tumour and normal cells which may implicate them pathologically. Genes involved and Proteins Gene TP53 Name Note Consistent somatic mutation of coding sequence in primary tumours is

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -530- strong evidence that a particular gene has been or is involved in the development of a neoplastic phenotype. In common with many tumour types, mutation of the TP53 gene is frequent in SCLC, occurring in ~80% of primary lesions.

Gene PTEN Name Note Chromosomal loss involving 10q24-26 is commonly seen in SCLC which suggests that this region may contain a disease-relevant tumour suppressor. Alterations (point mutations, small deletions) of the PTEN gene, located at 10q23.3, were observed in 18% of SCLC cell lines and 10% of primary tumours. PTEN encodes a lipid phosphatase which influences cell survival through signalling down the phosphoinositol-3- kinase/Akt pathway.

Gene MYC family Name Note Amplification of chromosomal bands 1p32, 2p23 and 8q24.1, regions encoding respectively MYCL, MYCN and MYC has been observed by CGH. The tendency for these genes to be amplified in SCLC has been confirmed through the use of gene-specific probes. The consistent involvement of these related but geographically disseminated sequences suggests that deregulation of some aspect of MYC function is important in SCLC pathogenesis and/or drug resistance. The MYC gene encodes a transcription factor which promotes cell proliferation by inducing the activation of growth-promoting genes and perhaps by inducing the repression of growth-suppressing sequences.

Gene RB1 Name Note Abnormal expression and/or mutation of the genes controlling progression through the G1 phase of the cell cycle occurs in many tumours. Two genes which negatively regulate this progression are RB1 and CDKN2A. In almost all cases of SCLC, the product of RB1 (the retinoblastoma protein, pRB) is not expressed as a consequence of deletion, mutation, chromosomal loss or other mechanisms. Conversely, and somewhat in contrast to NSCLC, the expression of the product of CDKN2A, the cyclin dependent kinase inhibitor p16, is generally retained in the tumour cells. The p16 protein negatively regulates cell cycle progression by blocking the phosphorylation of pRB by cyclin dependent kinases 4 and 6. The lack of a functional pRB protein in SCLC cells probably explains the lack of mutational and epigenetic inactivation of p16 in those cells.

Bibliography MYC family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -531- regimens. Brennan J, O'Connor T, Makuch RW et al. Cancer Res. 1991; 51: 1708-1712 Medline 1847842

High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. D'Amico D, Carbone D, Mitsudomi T et al. Oncogene 1992; 7: 339-346 Medline 1312696

Pathology of the Lung: second edition Thurlbeck WM and Churg AM (Eds) Thieme Medical Publishers, Inc. NY; 1995 ISBN 0-86577-543-6

Advances in the analysis of chromosome alterations in human lung carcinomas. Testa JR, Liu Z, Feder M, et al. Cancer Genet Cytogenet 1997; 95: 20-32 Medline 9140450

PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Yokomizo A, Tindall DJ, Drabkin H et al. Oncogene 1998; 17: 475-479 Medline 9696041

Classification of small cell lung cancer and pulmonary carcinoid by gene expression profiles. Anbazhagan R, Tihan T, Bornman DM, et al. Cancer Res 1999; 59: 5119-5122 Medline 10537285

Expression of p16 and lack of pRB in primary small cell lung cancer. Yuan J, Knorr J, Altmannsberger M, Goeckenjan G et al. J Pathol 1999; 189: 358-362 Medline 10547597

Lung Cancer: Principles and Practice Pass HI, Mitchell JB, Johnson DH Lippincott Williams & Wilkins, Philadelphia (pubs); 2000 ISBN 0-7817-1791-4

Chromosomal imbalances in human lung cancer. Balsara BR and Testa JR. Oncogene 2002; 21: 6877-6883 Medline 12362270

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Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Zabarovsky ER, Lerman MI, Minna JD. Oncogene 2002; 21: 6915-6935 Medline 12362274

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Jim Heighway, Daniel C Betticher 2004 Citation This paper should be referenced as such : Heighway J, Betticher DC . Lung: small cell cancer. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/LungSmallCellID5142.html

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Kidney: Clear cell renal cell carcinoma

Identity Other Common renal cell carcinoma names Conventional renal cell carcinoma Non papillary renal cell carcinoma Classification Clear cell renal cell carcinoma (cRCC) is a distinct subtype of renal cell carcinoma, possibly originating from mature renal tubular cells in the proximal tubule of the nehpron. Clinics and Pathology Epidemiology It comprises 70-75% of cases.They show a male preponderance of 2:1. Pathology The tumor mass of cRCC is multicolored, with a predominantly yellow surface with white or gray foci. It usually shows a solid growth pattern, but in some cases cystic or alveolar appearance is seen. The cytoplasm is clear, due to an intensive intracytoplasmatic accumulation of glycogen and lipids. The nuclei are condensed and hyperchromatic. Electronmicroscopical features resembling the proximale tubule can be found i.e. brush border formation and basal infoldings. Tumor cells express antigens of the proximal tubule.

Variants can be assigned which are characterized by augmentation of mitochondria leading to a stronger eosinophilia or granularity, respectively, of the cytoplasm. Spindle-shaped/pleomorphic variants as a result of sarcomatoid transformation can also be found. Cytogenetics Cytogenetics cRCC is characterized by loss of (part of) the short arm of Morphological chromosome 3 due to (a) deletion(s) or unbalanced translocation(s) and restricted to this type. Regions frequently lost are 3p12-14, 3p21 and 3p25. Loss of at least two of these regions is necessary for kidney cells to develop into clear cell renal cell carcinoma, and loss of 3p21 is obligatory. Therefore, if a tumor shows only one deletion at 3p, either 3p14 or 3p25, it should be designated common type renal cell adenomas.

Other aberrations frequently found in common RCC are (partial)

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -534- trisomy of chromosome 5, especially the 5q22-qter segment. Trisomy 12, and 20, and loss of chromosomes 8, 9, 13q, 14q, and structural abnormalities of the long arm of chromosomes 6 and 10 are also found and correlated with progression.

In general, cRCCs are sporadic tumors but also syndromic in patients with the von Hippel-Lindau (VHL) disease (germ line mutations in the VHL tumor suppressor gene assigned to 3p25). Also familial cRCC familial cRCC has been reported. All have in common the presence of abnormalities involving chromosome 3. Genes involved and Proteins Note Based on allele-segregation, LOH and mutation analyses, a step-wise model for cRCC tumorigenesis was put forward in which the loss of the translocation derivative chromosome 3 may lead to chromosomal mosaicism. Subsequently, cells lacking this chromosome may suffer a second hit resulting in full blown tumor development.

Loss of heterozygosity (LOH) and comparative genetic hybridization (CGH) analyses of cRCCs revealed that allelic (interstitial) losses predominantly occur in the chromosome 3p21 region in combination with either 3p25 or 3p13-14, or with both, and these allelic losses were restricted to the cRCC. These results suggest that loss of the 3p21 region is a prerequisite for malignant development of cRCC and indicate that several regions (and thus several genes) on human chromosome 3 contribute to cRCC tumor development.

Until today no tumor suppressor gene responsible for, or at least contributing to, cRCC has been identified -except for VHL-, in the different regions, although many candidate genes have been suggested such as FHIT (fragile histidine triad); TTRC1 (two-three-renal-cancer-1; DUTT1 (deleted in U-twenty twenty); locus NCR-1 (nonpapillary renal cell carcinoma 1) and RASSF1A (RAS association family 1).

The gene in the 3p25 region involved in cRCC development is the von Hippel Lindau (VHL) tumor suppressor gene. Somatic mutations and LOH of the VHL gene were also found in primary sporadic cRCCs. Occurrence of mutations in this gene in both sporadic as well as hereditary forms of cRCC suggests a key role of the VHL gene in oncogenesis. However, VHL is inactivated in only 30-50% of sporadic cRCC, suggesting involvement of another tumor suppressor gene located on 3p.

Loss of heterozygosity on chromosomes 8p or 9p provide prognostic significance in patients with locally advanced cRCC and PTEN/MMAC1 (chromosome 10) inactivation may play a role in the progression of cRCC.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -535-

To be noted Some first array studies on RCC have recently been published showing that specific gene expression patterns could be associated with various tumors (types) including cRCC and other disease states. Bibliography

Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas. Kovacs G, Kung HF. Proc Natl Acad Sci USA 1991; 88: 194-198. Medline 1986366

Identification of the von Hippel-Lindau disease tumor suppressor gene. Latif F, Tory K, Gnarra J, et al. Science 1993; 260: 1317-1320. Medline 8493574

Somatic mutations of the von Hippel-Lindau disease tumor suppressor gene in non-familial clear cell renal carcinoma. Foster K, Prowse A, van den Berg A, et al. Hum Mol Genet 1994; 3: 2169-2173. Medline 7881415

Frequent somatic mutations and loss of heterozygosity of the von Hipppel- Lindau tumor suppressor gene in primary renal cell carcinomas. Shuin T, Kondo K, Torigoe S, et al. Cancer Res 1994; 54: 2852-2855. Medline 8187067

Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal cell carcinoma. Gnarra JR, Duan DR, Weng YK, et al. Biochim Biophys Acta 1996; 1242: 201-210. Medline 8603073

The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Ohta M, Inoue H, Cotticelli MG, et al. Cell 1996; 84: 587-597. Medline 8598045

Involvement of multiple loci on chromosome 3 in renal cell cancer development. van den Berg A, Buys CHCM.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -536- Genes Chromosome Cancer 1997; 19: 59-76. Medline 9171996

Normal FHIT transcripts in renal cell cancer- and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region. van den Berg A, Draaijers TG, Kok K, et al. Genes Chromosomes Cancer 1997; 19: 220-227. Medline 9258656

Duplication of two distict regions on chromosome 5q in non-papillary renal-cell carcinomas. Bugert P, von Knobloch R, Kovacs G. Int J Cancer 1998; 76: 337-340. Medline 9579569

Physical and functional mapping of a tumor suppressor locus for renal cell carcinoma within 3p12. Lott ST, Lovell M, Naylor SL, Killary AM. Cancer Res 1998; 58: 3533-3537. Medline 9721855

The DUTT1 gene, a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression. Sundaresan V, Roberts I, Bateman A, et al. Mol Cell Neurosci 1998; 11: 29-35. Medline 9608531

Classification of renal cell cancer based on (cyto)genetic analysis. van den Berg E, Dijkhuizen T. Contrib Nephrol 1999; 128: 51-61. Medline 10597377

Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma. Alimov A, Kost-Alimova M, Liu J, et al. Oncogene 2000; 19: 1392-1399. Medline 10723130

The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Dreijerink K, Braga E, Kuzmin I, et al. Proc Natl Acad Sci USA 2001; 98: 7504-7509. Medline 11390984

Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -537- Morrissey C, Martinez A, Zatyka M, et al. Cancer Res 2001; 61: 7277-7281. Medline 11585766

Renal cancer: cytogenetic and molecular genetic aspects. Meloni-Ehrig AM. Am J Med Genet 2002; 30: 164-172. (REVIEW). Medline 12407697

Genetic progression of renal cell carcinoma. Moch H, Mihatsch MJ. Virchows Arch 2002; 44: 320-327. (REVIEW). Medline 12404056

Allelic loss on chromosomes 8 and 9 correlates with clinical outcome in locally advanced clear cell carcinoma of the kidney. Presti JC Jr, Reuter WM, Russo P, Motzer R, Waldman F. J Urol 2002; 167: 1464-1468. Medline 11832771

Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Velickovic M, Delahunt B, McIver B, Grebe SK. Mod Pathol 2002; 15: 479-485. Medline 12011252

Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21). Bodmer D, Schepens M, Eleveld MJ, et al. Genes Chromosomes Cancer 2003; 38:107-116. Medline 12939738

Hereditary renal cancers. Choyke PL, Glenn GM, Walther MM,et al. Radiology 2003; 226: 33-46. (REVIEW). Medline 12511666

Genetics in renal cell carcinoma. Dal Cin P. Curr Opin Urol 2003; 6: 463-466.(REVIEW) Medline 14560139

Chromosome 3 translocations and the risk to develop renal cell cancer: a Dutch intergroup study. Van Erp F, Van Ravenswaaij C, Bodmer D, et al. Genet Couns 2003;14: 149-154.(REVIEW)

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Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Higgins JP, Shinghal R, Gill H, et al. Am J Pathol 2003 Mar; 162: 925-932. Medline 12598325

Genetic subtyping of renal cell carcinoma by comparative genomic hybridization. Junker K, Weirich G, Amin MB, et al. Recent Results Cancer Res 2003; 162: 169-175. Medline 12790331

Prognostic factors in renal cell carcinoma. Kontak JA, Campbell SC. Urol Clin North Am 2003; 30: 467-480.(REVIEW) Medline 12953749

Patterns of aneuploidy in stage IV clear cell renal cell carcinoma revealed by comparative genomic hybridization and spectral karyotyping. Pavlovich CP, Padilla-Nash H, Wangsa D, et al. Genes Chromosomes Cancer 2003; 37: 252-260. Medline 12759923

The genetic basis of renal cell carcinoma. Pavlovich CP, Schmidt LS, Phillips JL. Urol Clin North Am 2003; 30: 437-454, vii. (REVIEW) Medline 12953747

Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma. Sukosd F, Kuroda N, Beothe T, et al. Cancer Res 2003; 63: 455-457. Medline 12543802

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers. Takahashi M, Yang XJ, Sugimura J, et al. Oncogene 2003; 22: 6810-6818. Medline 14555994

The allelic loss of chromosome 3p25 with c-myc gain is related to the development of clear-cell renal cell carcinoma. Yamaguchi S, Yoshihiro S, Matsuyama H, et al. Clin Genet 2003; 63: 184-191.

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Molecular genetics of kidney cancer. Zimmer M, Iliopoulos O. Cancer Treat Res 2003;116:3-27. (REVIEW) Medline 14650823

World Health Organization Classification of Tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Eble JN, Suter G, Epstein JI, Sesterhen IA (Eds) IARC Press: Lyon 2004 Chapter 1 Tumours of the kidney. Renal cell carcinoma. Clear cell renal cell carcinoma. pp 23-25.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Eva van den Berg, Stephan Störkel 2004 Citation This paper should be referenced as such : van den Berg E, Störkel S . Kidney: Clear cell renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/ClearCellRenalCC5020.html

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"Deep insight" into microarray technology

Claudia Schoch, Martin Dugas, Wolfgang Kern, Alexander Kohlmann, Susanne Schnittger, Torsten Haferlach

Laboratory for Leukemia Diagnostics, Dept. of Internal Medicine III, University Hospital Grosshadern, Marchioninistr. 15, 81377 Munich, Germany e-Mail: [email protected]

May 2004

So far the classification of tumors relies on the interpretation of clinical, histopathological, immunophenotypic, cytogenetic and molecular genetic findings. Especially in hematological tumors a precise analysis of the malignant cells using classical methods such as cytomorphology and histology which both are supplemented by cytochemistry and multiparameter immunophenotyping are used in routine diagnostics for classification. Furthermore, insights into the genetic basis of the disease, i.e. disease-specific chromosomal aberrations and molecular alterations detected in the malignant cell clone, have substantially increased the importance of cytogenetics, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) and their combination in establishing the diagnosis in each subentity. In the clinical setting this not only implies a better understanding of the course of distinct disease subtypes but also allows the selection of disease- specific therapeutic approaches, e.g. the use of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia or of imatinib in chronic myeloid leukemia. This is also true for an early application of allogeneic transplantation strategies in AML with complex aberrant karyotypes. Given this genetic background the microarray technology may become an essential tool for the optimization of the classification of tumors and thus may be used as a routine method for diagnostic purposes in the near future.

Microarray technology

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -541- In general two different fields in microarray based techniques can be distinguished: those approaches dealing with copy number changes on the DNA level – so called Array- or Matrix-CGH (comparative genomic hybridization) – and those approaching gene expression measuring changes at the RNA level.

Array based CGH

Conventional comparative genomic hybridization (CGH) is a technique based on the use of genomic DNA as a probe. It provides an overview of DNA sequences copy number changes (losses, deletions, gains, amplifications) in a specimen and maps theses changes on normal chromosomes.1,2 CGH is based on the in situ hybridization of differentially labeled total genomic test DNA and control reference DNA to normal human metaphase chromosomes. Copy number variations among the different sequences in the tumor DNA are detected by measuring the test/control fluorescence intensity ratio for each locus in the normal metaphase chromosomes. CGH only detects changes that are present in a substantial proportion of cells (>50%). It does not reveal translocations, inversions and other aberrations that do not change copy numbers. Therefore, CGH allows the comprehensive analysis of the entire genome in just one experiment providing information not only about the size of all chromosomal imbalances but also on their chromosomal band specific assignment. Using the conventional CGH approach hybridizing test and control DNA on metaphases the resolution is limited to the cytogenetic band resolution, approximately 5-10 Mb for deletions and 2 Mb for amplifications. In 1997, Solinas-Toldo and co-workers established a matrix-based CGH array that replaces condensed metaphase chromosomes by defined cloned DNA probes immobilized on a glass surface as hybridization target, allowing automated analysis of genetic imbalances such as microdeletions and overrepresentations.3 This technique was called array CGH by others.4 More details on strategies for constructing these type of arrays and technical aspects are reviewed by Mantripragada et al. and Ishkanian et al..5,6

Gene expression analysis based on microarray technology

Gene expression analyses using microarrays have become an important part of the biomedical basic and clinical science. Common to all microarray approaches is the basic principle of complementary base pairing. Complementary nucleotide strands interact non-covalently and then can be detected.7 By the application of gene expression profiling the present gene expression status of a cell or a cell population is used to build a molecular fingerprint. To allow this the respective gene sequences are coated on a solid layer at high density. Thus, performing

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -542- only one experiment the expression status of thousands of genes can be assessed simultaneously. Using specific software packages a judgement on the respective genes with regard to its expression is possible for distinct time points or disease states. Moreover, besides the qualitative assessment the results can be evaluated also quantitatively which may be highly relevant both in the pathogenesis of a malignant disease and for its clinical management as has been shown for the overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer. Gene expression profiles thus provide a molecular fingerprint of the transcriptome. If and when genes are expressed, however, is influenced by many developmental and tissue-specific factors.

Microarray platforms for gene expression analysis

Two basically different methods are available: desoxyribonucleic acid oligonucleotide (DNA) microarrays and arrays spotted with complementary DNA (cDNA) (figure 1). Gene-specific sequences are synthesized in situ at defined positions on the DNA-oligonucleotide microarrays.8 The sample to be analyzed (5 µg total ribonucleic acid (RNA), which is equivalent to 1 to 8 x 106 cells) is translated into cDNA and subsequently amplified in an in vitro transcription. During this process biotinylated ribonucleotides are incorporated by the T7-RNA- polymerase into the growing cRNA strands. Per single experiment 10 µg fragmented and biotin-labeled cRNA are hybridized to the microarray. After staining of the DNA-cRNA hybrides using streptavidin- phycoerythrin their detection is accomplished by an argon laser (figure 2). On the present HG-U133A+B microarray (Affymetrix) for example about 33,000 human genes are represented each by 11 different oligonucleotides. In addition, sequence-specific oligonucleotides carrying a central point mutation are used as an internal mismatch control. The results obtained by this approach are highly reproducible. Optimizing the homogeneitity of the cellular composition to which the microarray technology will be applied is essential for the selection of the respective samples. A significant mixture of malignant and non- malignant cells may lead to hybridization results not exactly reflecting the expression levels present in the tumor. Thus, microdissection of single tumor cells is applied in some analyses of solid tumors.9

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Figure 1 : The test (i.e. tumor) DNA and the control (i.e. normal) DNA are labeled with different fluorochromes and Cot-1 DANN is added. This mixture is hybridized onto the microarray. Appropriate software is used to calculate fluorescent intensity ratios that reflect genomic imbalances between test and control DNA. A ratio of 1 indicates equal copy numbers of genomic regions in the test and the control DNA. Deviations from this ratio are indicative of either gains or losses in the test genome.

Figure 2 : After staining of the DNA-cRNA hybrides (A) using streptavidin-phycoerythrin their detection is accomplished by an argon laser resulting in a probe array image (B) containing raw signal expression intensities.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -544- Spotted cDNA-Arrays are applied mostly for specific questions defined by the user targeting on a selected number of gene sequences which are brought onto the respective surfaces as cDNA (e.g. glas slide, nylon membrane).10 The RNA of interest and a control RNA are then labeled by different fluorochromes and co-hybridized. This approach allows greater flexibility in single analyses as compared to the predefined whole genome DNA-oligonucleotide microarrays. However, more experience and skills are needed, with regard to the selection of sequences, the optimization of protocols for hybridization and washing procedures, the manufacturing of the array and the reproducibility in general.

For both methods the detection of the hybridization signals requires a specific microarray scanner connected to a database which is essential for the analysis of the large amount of data. In addition, various algorithms must be applied to optimize the evaluation of the data.

Bioinformatics, data management, and functional annotation

Microarray data is characterized by a large number (typically >20.000) of measurement values per patient sample. It is difficult to be interpreted, because the number of genes is much higher than the number of samples and the data correlation structure is not well understood. Therefore the challenge is to distinguish between random and significant patterns of gene expression. Clinical data is complicated, too. There are many different items, both quantitative and categorical, often with complex coding schemes. Clinical data is multi- dimensional, because each clinical data source (e.g. a specific lab technique) provides a different view on the same patient. For this reason a systematic approach in data management with detailed planning and documentation is strongly recommended to keep an overview with microarray analysis in a clinical setting. Microarray studies generate vast quantities of data. Even small studies easily sum up to several gigabytes of raw expression data. Several steps have to be performed before the raw data are in shape for a biological or clinical evaluation. After quality control of the sample and the hybridization, image processing, translation of images into signal intensities and normalization data is prepared for data mining.

Quality control (QC) is a key issue in microarray analysis. It should be addressed both from a biological and a bioinformatic perspective. First, one should always look at the raw data, i.e. scanned chip images, to identify artifacts. QC parameters recommended by the microarray manufacturer should be assessed, for instance in Affymetrix arrays 3'/5' ratios for selected genes and percentage of "present calls". Reproducibility of microarray measurements should be assessed.

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -545- After image processing, the first analysis step is to produce a large number of quantified gene expression values. These values represent absolute fluorescence signal intensities as a direct result of hybdridization events on the array surface. It is also possible to qualitatively rate gene expression as absent/present detection call calculations.9,11 Before analyzing the data it is a routine procedure to normalize the raw data.12 This is a mandatory step in the data mining process in order to appropriately compare the measured gene expression levels. From the same experiments several data sets and lists of significant genes may be derived by different data normalization/calibration methods. Affymetrix chip data can be transformed by different techniques, for instance mas5 (http://www.affymetrix.com) or rma [http://www.bioconductor.org].13 In addition, there are preprocessing techniques like global scaling, quantile normalization (dchip),14 variance stabilization (vsn) 15 and others. So far there is no generally accepted gold standard for quality control and data calibration.

Data mining, the discovery of non-obvious information, often uses mathematical techniques that have traditionally been used to identify patterns in complex data. Recently, they have been adapted for functional genomics needs. There are two different approaches to analyze the data, i.e. the unsupervised approach and the supervised approach. An unsupervised analysis does not use any a priori class definition, instead simply seeks to determine what structure is inherent in the data. A supervised analysis aims at uncovering putative associations. Therefore, it may bias the outcome by forcing a model onto the data.

Unsupervised analysis

Unsupervised analysis of microarray data aims to detect groups of samples or outliers without knowledge of the clinical features of each sample. For instance new subgroups of a disease with consistent "molecular signature" can be identified. Commonly used methods are principal component analysis (PCA)16 and hierarchical clustering.17 PCA reduces dimensionality of the data set while retaining most of information contained therein via construction of a linear transformation matrix. Principal components are the projections of the data on the eigenvectors. In figure 3 each point corresponds to one patient; its coordinates are derived from the principal components. Hierarchical clustering is an unsupervised method for organizing expression data into groups with similar signatures (figure 4). There are several methods to calculate similarity (euclidean, manhattan, pearson) and several procedures to link similar sets of samples (single, average and complete linkage). Consequently, several different hierarchical clusterings can be generated from the same microarray data set, which may complicate interpretation. Hierarchical clustering can be used to

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -546- reduce the complexity of the matrix-like data and to visualize it in a more understandable way. Patterns in the data are discovered solely from the data itself as there is no previous knowledge or grouping of the data. Two-dimensional hierarchical clustering sorts both patients and genes according to similarities and leads to a tree-structured dendrogram which can easily be viewed and explored.17 It is clear that this hierarchical structure provides potentially useful information about the relationship between adjacent clusters. Common crossing points represent similar patient characteristics as well as similarities with regard to the co-expression of distinct genes.17 It has to be kept in mind that both PCA and hierarchical clustering can be strongly influenced by selection of genes.

Figure 3 : Principal components are the projections of the data on the eigenvectors. In figure 3 a principal component analysis is shown based on gene expression signatures from n=800 genes which we identified to be differentially expressed when analysing AML samples with t(15;17) (n=40), t(8;21) (n=40), inv(16) (n=40), t(11q23)/MLL (n=40), or complex aberrant karyotypes (n=40). In the three-dimensional graph data points with similar characteristics will cluster together. Here, each patient´s expression pattern is represented by a single color-coded sphere. The feature space consisted of measured expression data from n=800 genes. The respective karyotype label, i.e. t(15;17),

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -547- t(8;21), inv(16), t(11q23)/MLL, or complex aberrant was unknown to the algorithm. The labels and coloring of the classes were added after the analysis for means for better visualization. AML patients with t(15;17) are colored blue, t(8;21) red, inv(16) yellow, t(11q23)/MLL turquoise, and complex aberrant karyotype cases pink, respectively.

Figure 4 : Hierarchical cluster analysis is a popular unsupervised method for arranging genes and patients according to underlying similarities in patterns of gene expression. In figure 4 a hierarchical clustering based on U133A microarray expression data of our adult AML samples (columns) is shown. This analysis is based on a subset of n=800 genes (rows) which we identified to be differentially expressed when analysing AML samples with t(15;17) (n=40), t(8;21) (n=40), inv(16) (n=40), t(11q23)/MLL (n=40), or complex aberrant karyotypes (n=40). The normalized expression value for each gene is coded by color (standard deviation from mean). Red cells indicate high expression and green cells indicate low expression. The respective karyotype label, i.e. t(15;17), t(8;21), inv(16), t(11q23)/MLL, or complex aberrant was unknown to the algorithm. The labels and coloring of the classes were added after the analysis for means for better

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -548- visualization. AML patients with t(15;17) are colored blue, t(8;21) red, inv(16) yellow, t(11q23)/MLL turquoise, and complex aberrant karyotype cases pink, respectively.

Supervised analysis

Typically, it is of great interest to correlate array data directly with e.g. clinical, cytomorphological, or cytogenetic features. In supervised analysis the diagnosis or classification of each sample is known. The key issue of this evaluation is to identify significant differentially expressed genes. Usually classical biostatistical methods are applied, in particular t-test, ANOVA, correlation and regression methods. Given the large number of genes, results should be adjusted for multiple testing to exclude random patterns. A common approach is calculation of the false discovery rate (FDR),18 which is available in the SAM [http://www-stat.stanford.edu/~tibs/SAM/] and q-value software.18,19 There are different types of clinical response variables: Categorical (for example diagnosis A,B,C), quantitative (like creatinine level) and survival (e.g. disease-free survival time + survival-status). In each type of supervised analysis, a list is generated containing genes associated with the clinical response variable. The number of significant genes is determined by the choice of significance level.

Classification based on gene expression data

After detecting differential gene expression it is often necessary to accurately classify samples into known groups. There are quite a few methods to classify samples for instance support vector machines (SVM),20 PAM,21 classification and regression trees (CART), k- Nearest-Neighbor (k-NN) and others. There is evidence that SVM- based prediction slightly outperforms other classification techniques.22,23 To estimate diagnostic accuracy, the prediction model is built using a training set of patient samples. Accuracy is determined based on predictions in an independent test set. Apparent accuracy usually is determined by 10-fold crossvalidation (10-fold CV): The data set is divided into 10 approximately equally sized subsets, the prediction model is trained for 9 subsets and predictions are generated for the remaining subset. This training / prediction process is repeated 10 times to include predictions for each subset. Apparent accuracy is the overall rate of correct predictions. Random sets of training and test data can be generated iteratively to assess robustness of diagnostic accuracy. Since most software packages still rely on strong informatic/statistic knowledge and programming skills robust, intuitive and user-friendly software is needed. Bioconductor, for example, is an open source and open development software project to provide tools for

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -549- the analysis and comprehension of genomic data (www.bioconductor.org/).

Functional Annotation

By use of detailed gene annotation it is possible to find functional groupings of genes based on their similarity among the gene expression profiles. This information can be used to get new insights into physiological pathways and may also help to characterize previously uncharacterized genes.17 A structured and normalized annotation of the respective genes and gene products, essential for all evaluations, is provided by the Gene Ontology™ consortium.24 The three principles of organization and possibilities for the annotation are based on the description of the molecular function of the gene product (e.g. enzyme or transporter), of the biologic process in which one or more molecular functions are involved (e.g. cell growth or signal transduction), and on an assignment of the cellular localization (e.g. nucleus or integral membrane protein). In addition, detailed hierarchical models are provided, e.g. the metabolism of DNA is further separated into replication and repair of DNA. Public available databases like NetAffx provide regularly updated functional gene annotations.25 Furthermore, relevant gene informations are connected to other various databases like OMIM (www.ncbi.nlm.nih.gov/omim/), SWISSPROT (http:/us.expasy.org/sprot/) and thereby substantiate the biologic knowledge about a gene and its gene product and facilitate the interpretation of microarray experiment results. Another way of accelerating the pace of data analysis is to approach the data from a higher level of organization instead from a gene-by-gene basis. MAPPfinder is such a useful application and integrates and links GO™ annotations to array expression data allowing to identify gene expression changes directly on particular pathways. 26,27

The effective annotation of microarray experiments is a major task which is approached by the MGED group (Microarray Gene Expression Data Group, www.mged.org).28 This consortium defines standards for the annotation of microarray experiments (MIAME, Minimum Information About a Microarray Experiment) as well as a standard data- exchange format (MAGE-ML, Microarray Gene Expression Markup Language). Based on these standards global expression databases have been established with the aim to give access to, to share and to compare microarray data. In accordance with the MGED recommendations, ArrayExpress (www.ebi.ac.uk/arrayexpress) is such a public repository for microarray data. The NCBI has launched the Gene Expression Omnibus (GEO), a gene expression and hybridization array data repository, as well as an online resource for the retrieval of gene expression data from any organism or artificial source (www.ncbi.nlm.nih.gov/geo/).

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -550-

Biological networks analysis

In order to evaluate the role of significantly deregulated genes in the pathogenesis of a certain disease the question arises whether some of these genes are involved in a common pathway. Such biological networks can be generated through the use of Ingenuity Pathways Analysis, a web-delivered application that enables scientists to discover, visualize and explore therapeutically relevant networks significant to their experimental results, such as gene expression array data sets. For a detailed description of Ingenuity Pathways Analysis, visit www.ingenuity.com.

First, genes have to be identified whose expression is significantly differentially regulated between two groups. For generating molecular networks that indicate how these genes may influence each other a cut- off of i.e. 5% FDR (q-value < 0.05) can be set. This data set containing gene identifiers and their corresponding expression signal intensities can be uploaded as a tab-delimited text file into the Ingenuity Pathways Knowledge Base. Then each probe set is automatically mapped to its corresponding data base gene object to designate so-called focus genes. Focus genes are genes from the analysis input data file that meet both of the following criteria: These genes have been designated as being of interest, i.e. a certain level of significance. They directly interact with other genes in the Ingenuity global molecular network, which consists of direct physical, enzymatic, and transcriptional interactions between mammalian orthologs from the published, peer- reviewed content in Ingenuity’s Pathways Knowledge Base (IPKB).

To start building the networks, the application queries the Ingenuity Pathways Knowledge Base for interactions between focus genes and all other gene objects stored in the knowledge base, and generates a set of networks with a network size of 35 genes/gene products. The application then computes a score for each network according to the fit of the user’s set of significant genes. The score is derived from a p- value and indicates the likelihood of the focus genes in a network being found together due to random chance. A score of 2 indicates that there is a 1 in 100 chance that the focus genes are together in a network due to random chance. Therefore, scores of 2 or higher have at least a 99% confidence of not being generated by random chance alone. Biological functions are then calculated and assigned to each network.

The networks are displayed graphically as nodes (genes/gene products) and edges (the biological relationships between the nodes). The intensity of the node color indicates the degree of up- (green) or down- (red) regulation. As described in the legend provided, nodes are displayed using various shapes that represent the functional class of the gene product. Edges are displayed with various labels that describe the nature of the relationship between the nodes (e.g., B for binding, T

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -551- for transcription). The length of an edge reflects the evidence supporting that node-to-node relationship, in that edges supported by more articles from the literature are shorter. Two examples are shown in figures 5 and 6.

Figure 5

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -552-

Figure 6

Liang et al. propose an approach going even further stepping from gene expression profiling to integrative physiology.29

Results of microarray analyses

Results of genomic imbalances assessed by array based CGH

The sensitivity and quantitative capability of array based CGH for the measurement of gene dosage was analyzed by Pinkel et al..4 In the same study it was demonstrated that this technique was useful to detect DNA copy number aberrations in cancer. The first genome-wide array based CGH analysis of DNA gains and losses was performed in breast cancer.30

In chronic lymphocytic leukemia recurrent known as well as new genomic alterations were identified using array based CGH.31 Several studies analysed DNA copy number changes in breast cancer. Array based CGH provided a higher resolution mapping of already known amplicons and revealed that amplicons are either simple or very complex, either showing a simple peak, i.e. the amplicon encompassing ERBB2 or in contrast the 11q amplicon showing a complex pattern with amplification of CCND1 usually accompanied by amplifications of

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -553- several distinct adjacent copy number peaks as well as loss of copy number.32 Also studies on classification of renal cell cancer, gastric cancer and liposarcoma based on copy number profiles assessed by array based CGH have been reported.33,34

Some studies have already been performed using genome wide array based CGH in combination with global gene expression profiling and found a good correspondence between copy number alterations and changes in gene expression.35,36 In a study of liposarcoma, copy number profiles had a greater power to discriminate between dedifferentiated and pleomorphic subtypes than expression profiling.37

Gene expression data

A magnitude of different questions was approached by microarray based gene expression analyses during the last years. Besides new insights into the pathophysiological and ontogenetic context 38 data on malignant diseases in particular are of high interest. Following the pivotal work of Golub et al. who provided data on the applicability of microarrays and new biostatistical methodologies 39 even more detailed analyses were performed. The published data can be separated in categories addressing different aspects: aim of

a) reproducibility of data on different array platforms or different technologies, b) “class prediction“ (prediction of a tumor entity based on specific gene expression profiles of selected informative genes), c) “class discovery“ (discovery of new subentities within groups formerly regarded as homogeneous), d) prediction of prognosis, e) prediction of response to therapy and f) new insights into the pathogenesis.

During the recent months a large number of original papers as well as reviews on gene expression analysis in leukemia have been published. Therefore, only a few examples are mentioned highlighting the different aspects gene expression analysis based on microarrays can address.

One of the first studies applying the microarray technology to leukemia has been performed by Golub et al. who demonstrated that both ALL and AML are characterized by a distinct and specific gene expression profile. In a pilot study bone marrow samples of 27 patients with ALL and 11 patients with AML have been analyzed and discriminatory genes were identified allowing the distinction of both of these large entities of leukemias based on their gene expression profiles. A total of 50 genes had been sufficient to classify acute leukemias in this study: in 36 of 38 cases the molecular diagnosis of leukemia was made

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -554- correctly based on the gene expression profile as analyzed on the microarray. In a further set of 34 unknown samples which had not been used to build up the classification model the classification was also correct in the majority of cases, i.e. 29 cases were assigned correctly. These analyses represent the first and a major step towards molecular diagnostics of acute leukemias.39

Another report dealt with the question if AML with trisomy 8 as the sole cytogenetic aberration can be separated from AML with a normal karyotype based on the gene expression profile.40 However, in this analysis a totally correct separation has not been possible which may be due to trisomy 8 not being the primary lesion leading to AML but rather a secondary aberration in addition to a molecular event. Nonetheless, a gene dosage effect could be clearly demonstrated since many genes which are coded on the chromosome 8 showed an elevated gene expression in general. This effect of gene dosage on gene expression has been confirmed and was in addition also shown for trisomy 11 and trisomy 13 as well as for monosomy 7 and deletion 5q in AML.

A different aspect with respect to the relationship between genetic abnormalites on the genomic level and gene expression was addressed in several studies. It was demonstrated that cytogenetically defined subtypes in AML such as AML with t(8;21), AML with t(15;17), and AML with inv(16) are characterized by different and specific gene expression profiles.41 The basic genetic alterations lead to patterns of gene expression that can be unequivocally detected by microarrays. A minimum set of only 13 genes has been sufficient to accurately predict the karyotypes in the respective AML samples.41 In a next step the analyzed cohort has been extended by eight samples with normal bone marrow. In this setting the expression profiles of 35 genes were sufficient to predict with an accuracy of 100% if the sample contained normal bone marrow, AML M2 with t(8;21), APL with t(15;17), or AML M4eo with inv(16).42 A further step consisted in the addition of samples with AML carrying aberrations of chromosome 11q23, i.e. MLL gene rearrangements, representing an analysis of AML subtypes with recurring chromosomal aberrations as defined by the WHO.43,44 In this analysis a minimum set of 39 genes has been sufficient to classify based on the gene expression profile samples as normal bone marrow or AML with one of the aberrations t(8;21), t(15;17), inv(16), or 11q23- rearrangements. Thus, the differential expression of these 39 candidate genes is sufficient to classify cytogenetically defined subtypes of AML and to separate these from normal bone marrow. The accuracy of this classification as determined by a leave-one-out crossvalidation amounts to 100%.

Also in ALL data demonstrate that subtypes characterized by specific genetic abnormalities show distinct gene expression profiles. Armstrong et al. were the first to demonstrate that childhood ALL with chromosomal aberrations involving the MLL gene can be regarded as a

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -555- molecularly defined entity distinct from other ALL.45 MLL-positive ALL had a distinct gene expression profile consistent with an early hematopoieteic progenitor expressing multilineage markers and specific HOX genes. Also the comparison of these ALL with MLL aberration with other ALL subtypes as well as with AML samples resulted in a clear separation of all three groups from each other.

Furthermore, the global gene expression profiles of ALL (n=10) and AML (n=15) both t(11q23)/MLL-positive was analyzed by Kohlmann et al. using U133A arrays (Affymetrix). Based on 20 top-ranked genes both leukemias were discriminated with a 100% accuracy (permutation- based neighborhood analysis).46

A milestone in microarray analysis with respect to class discovery, class prediction, prediction of outcome was the report by Yeoh et al. on 327 childhood ALL.47 Patients were discrimated according to their cytogenetic and immunological as well as to their molecular subtype of ALL, i.e. T-ALL, E2A-PBX1, BCR-ABL, TEL/AML1, MLL rearrangements, and hyperdiploid ALL. Many of the relevant genes were also verified in an analysis of corresponding adult ALL patients.48 As some patients were not classified according to these subgroups Yeoh et al. postulated a novel subgroup of ALL that was characterized by high expression of genes including the receptor phosphatase PTPRM and LHFPL2. Ross et al. rehybridized 132 childhood ALL probes using the Affymetrix U133 set and identified almost 60% of new discriminating genes in comparison to their previous analysis. As a proportion of these new genes were highly ranked as class discriminators and led to an overall diagnostic accuracy of 97% in several analyses the authors suggested to assess these genes expression profiles in a prospective clinical setting. The main clinical focus should be at diagnosis of ALL with respect to accuracy, practicality, and cost effectiveness in comparison to standard diagnostic techniques.

A pivotal work with regard to “class discovery” by microarrays was presented by Alizadeh et al. who showed that cases with diffuse large- cell B-cell lymphoma can be separated into two molecularly different groups based on their gene expression profiles. This separation of the formerly homogeneously regarded group in addition resulted in two groups with highly differing prognoses. Interestingly, one of these two new subgroups was characterized by a gene expression pattern which was closely related to follicular B-cells. In contrast, the other group was related to activated B-cells as present in the peripheral blood. Thus, these contributions clearly demonstrated the possibility by gene expression profiling to define new subclasses within entities formerly regarded as homogeneous.49 Further work also demonstrated the capability of this technique to separate a large variety of solid tumors.50

In another paper Yagi et al. analysed 54 pediatric AML focused on the reproducibility of morphological subtypes of AML and especially on

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -556- gene patterns to predict outcome.51 After unsupervised clustering they were able to differentiate patients with t(8;21) from those with inv(16), and from those demonstrating an AML M4/5, or AML M7 phenotype or immunophenotype by specific gene expression signatures. Within this unsupervised analysis no specific profile was found that correlated to the prognosis of the patients. Since the inclusion of further cases with other FAB subtypes and cytogenetic abnormalities (no karyotype available in 9 of 54 cases) resulted in an increased heterogeneity the authors restricted their further analyses to the genetically and morphologically better defined subentities. For further calculation data were analyzed supervised with respect to outcome and prognosis. A subset of 35 genes was selected that was independent from the morphology or karyotype of these patients, some of them are associated with regulation of the cell cycle or with apoptosis. By hierarchical cluster analysis patients could be classified into high-risk and low-risk groups with highly significant prognostics on EFS (p<0.001).

With respect to therapy response in ALL Hofmann et al. analyzed 25 bone marrow samples from 19 patients with Philadelphia-positive ALL all treated with the tyrosine kinase inhibitor imatinib using the HuGene FL arrays (Affymetrix).52 The patients in this study were selected according to their cytogenetic response to the drug and 95 genes were identified to predict the treatment outcome in their cohort. Another 56 genes were found to predict leukemia cells that had secondary resistance to the drug after remission had been achieved. These results point to further applications of microarray profiling leading to tailored therapy approaches and withhold therapies unlikely to induce remission. Especially in this field of gene expression profiling further studies with independent test cohorts are urgently needed.

In a recent study Cheok et al. examined gene expression profiles in 60 childhood ALL cases before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination.53 A total of 124 differentially expressed gene before and after the corresponding treatment were identified capable of accurately discriminating the four possible treatment groups. Genes included those involved in apoptosis, mismatch repair, cell-cycle control, and stress response. These data indicate that leukemia cells in different patients react in a similar matter after specific treatments and therefore share common pathways of genomic responses to different drug schedules.

It has further been published very recently that subdiscrimination in AML focussing on molecular markers such as FLT3-LM or CEPBA 54 and on prognostication in patients with normal karyotypes seems also possible by specific gene expression profils and sophisticated biomathematical approaches.55,56

Atlas Genet Cytogenet Oncol Haematol 2004; 3 -557- Future applications

Microarrays provide a means for the comprehensive and simultaneous analysis of the expression status of thousands of genes. The resulting signature allows the identification of a distinct molecular phenotype. It is anticipated that the application of microarrays will significantly improve molecular diagnostics and will provide deep insights into the pathogenetic alterations of malignant and non-malignant diseases which will allow the development of novel treatment approaches. To realize these efforts it is important to cover well-defined questions in well-classified tumor samples. Furthermore, it is expected that the results of microarray experiments will allow the identification of disease- specific target structures and the design of novel and specific drugs.

The comparisons of different gene expression analyses will provide answers for both diagnostic and biological questions. Besides the above mentioned reports on disease-specific gene expression profiles in a variety of malignancies even the potential of a primary tumor to progress into the metastatic status may be detected and predicted by microarray analyses.57 Gene expression analyses are limited, however, to the transcriptional level and thus cannot be used to analyze alterations at the protein level, e.g. the phosphorylation and dephosphorylation of proteins. These aspects will be covered by novel techniques like proteomics.

With regard to leukemia the microarray analysis represents a novel promising method which may be used as a diagnostic tool in the near future. Today the diagnosis and subclassification of leukemia is based on the application of various techniques like cytomorphology, cytogenetics, fluorescence in situ hybridization, multiparameter flow cytometry, and PCR-based methods which are time-consuming and cost-intensive and require expert knowledge in central reference laboratories. The microarray analysis serves the potential basis for the diagnosis of AML and other leukemias to be performed on a single platform at a high degree of validity and cost-effectiveness. Before this can be introduced into practice, however, extensive analyses will be necessary that compare the results of gene expression profiling with the results of methods considered standard for diagnostic purposes today.

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Contributor(s) Written 06- Claudia Schoch, Martin Dugas, Wolfgang Kern, Alexander 2004 Kohlmann, Susanne Schnittger, Torsten Haferlach Citation This paper should be referenced as such : Schoch C, Dugas M, Kern W, Kohlmann A, Schnittger S, Haferlach T. . "Deep insight" into microarray technology. Atlas Genet Cytogenet Oncol Haematol. June 2004 . URL : http://AtlasGeneticsOncology.org/Deep/MicroarraysID20045.html

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